The availability of single-cell transcriptomes and electron-microscopy connectomes in
Caenorhabditis elegans facilitates detailed perusal of expressed genes in every neuron of its
nervous system. In this report, I describe striking asymmetric arrangements of gap junction
proteins (innexins) forming electrical synapses between command interneurons (AVA, AVB,
RIB) and downstream motor neurons (VA, VB, SMB, SMD). A key feature of these motor
neurons is the presence of long, morphologically undifferentiated process regions situated
distally from neuromuscular junctions, hypothesized to function as proprioceptive stretch
receptors. The stoichiometric asymmetry and selective expression of putative rectifying
innexins (including unc-7, unc-9, eat-5, inx-19, and inx-21/22) at these electrical synapses
suggest that these junctions act as rectifying diodes. Such an arrangement would prevent
locally generated antidromic action potentials or self-stimulated motor activity from backpropagating
into central command interneurons.
","acknowledgements":"","authors":[{"affiliations":["Emeritus Professor, University of Wisconsin, Madison"],"departments":[""],"credit":["conceptualization","formalAnalysis","writing_originalDraft"],"email":"kc9fyh@gmail.com","firstName":"John","lastName":"White","submittingAuthor":true,"correspondingAuthor":true,"equalContribution":false,"WBId":null,"orcid":null}],"awards":[],"conflictsOfInterest":"The authors declare that there are no conflicts of interest present.
","dataTable":{"url":null},"extendedData":[],"funding":"No funding used
","image":{"url":"https://portal.micropublication.org/uploads/d16cda41f9b86b7f38e8e4e38fd7c0d5.png"},"imageCaption":"Figure 1 Legend. Expression asymmetry of gap junction innexins suggests a rectifying diode isolation mechanism between command interneurons and motor circuit processes.
(A) Innexin expression matrix in identified neurons. Single-cell RNA-seq expression levels (mean TPM, CeNGEN adult dataset; Taylor et al., 2021) of innexins (unc-7, unc-9, inx-21, inx-22, eat-5, and inx-19) in head motor neurons (SMB, SMD), body motor neurons (VA, VB), and associated interneurons (AVA, AVB, RIB, SAA). Bold values highlight dominant expression or key asymmetrical ratios. Note the pronounced unc-7/unc-9 expression ratio skew toward command interneurons (AVA: 6.15; AVB: 5.65; SAA: 3.87). The mean unc-7/unc-9 ratio for all co-expressing neurons in the organism is 1.60. AVB exhibits a high unc-7/unc-9 ratio together with selective expression of the asymmetric innexin inx-19. SAA also exhibits a high unc-7/unc-9 ratio together with selective expression of the asymmetric innexin eat-5. (B) Putative electrical synapses in body motor neuron circuitry. Schematic representation of asymmetric gap junctions between command interneurons (AVA, AVB) and ventral cord motor neurons (VA, VB). Heterotypic coupling between UNC-7 (interneuron side) and UNC-9 (motor neuron side), as well as selective INX-19 expression in AVB, suggests the presence of functional electrical diodes (indicated by diode symbols) configured to pass depolarizing current anterograde while blocking antidromic back-propagation (Starich et al., 2009; Liu et al., 2020). Green bars indicate the presence of distal, uninnervated process extensions hypothesized to function as proprioceptive stretch receptors (White et al., 1986; Wen et al., 2012). AVA also makes chemical synapses onto VA motor neurons (indicated by arrow). (C) Putative electrical synapses in head motor neuron circuitry. Circuit diagram showing asymmetrical gap junctions between head motor neurons (SMB, SMD) and head interneurons (RIB, SAA). EAT-5 is selectively expressed in SMB and SAA, while both INX-21 and INX-22 are selectively expressed in SMD, establishing distinct asymmetric electrical coupling in head motor neuron circuitry (Starich et al., 1996; Simonsen et al., 2014). RIB is a major hub interneuron of the central nervous system (White et al., 1986; Cook et al., 2019). The rectifying electrical connections to SMB and SMD act to isolate RIB from the back-propagation of local electrical activity produced by the proprioceptive activation of SMB and SMD. SAA makes a chemical synapse (arrow) onto SMD in addition to its electrical connection to SMB. (D) Process morphology of body motor neurons VA3 and VB4. Anatomical schematics depicting the extended, morphologically undifferentiated distal processes (green) of VA3 and VB4 extending beyond neuromuscular junction zones (red bars). (E) Process morphology of dorsal head motor neurons SMBDL and SMDDL. Anatomical schematics illustrating the process trajectories of SMBDL and SMDDL, highlighting distal sensory/proprioceptive extensions (green) relative to synaptic output regions within the nerve ring (red). These processes run down the length of the body in small sub-lateral cords. Cell bodies are shown in black. Panels (D) and (E) adapted from White et al. (1986).
","imageTitle":"Innexin asymmetries in motor neuron circuitry
","methods":"Methods
Transcriptomic and Connectomic Data Analysis
Single-cell RNA sequencing expression levels (Transcripts Per Million, TPM) for all 25 Caenorhabditis elegans innexins across 133 identified neuronal cell types were extracted from the adult CeNGEN dataset (Taylor et al., 2021). Co-expression frequencies and mean expression ratios were calculated using custom Python scripts running in Google Colab (Python 3.10; pandas v2.0, numpy v1.24). Neuronal co-expression of unc-7 and unc-9 was defined as non-zero TPM values (>0.0 TPM) in both genes across the 133 annotated neuron classes. Anatomical connectivity, chemical and electrical synapse counts, and motor neuron process morphologies were cross-referenced against the EM connectome datasets (White et al., 1986; Cook et al., 2019) and WormAtlas (Altun et al., 2009).
Computational Collaboration & AI Support
Large Language Model AI assistance (Gemini, Google) was utilized as a collaborative tool during manuscript preparation. Specifically, AI code execution environments were employed to write and run Python scripts for dataset parsing, co-expression statistics calculations, and matrix formatting. The AI was also used to assist with composite figure layout montaging (via matplotlib and PIL), reference formatting, and editorial polishing of text drafts under direct author supervision.
","reagents":"","patternDescription":"Description
The nervous system of C. elegans comprises a total complement of only 302 neurons, yet contains the foundational circuit principles of vertebrate nervous systems, which, in humans, contain about 86 billion neurons (Goriely, 2024). In the mid-1960s, Sydney Brenner pioneered the use of C. elegans as a genetic model system to dissect nervous system development and function (Brenner, 1974). Since then, extensive research has generated comprehensive datasets detailing both the structural connectivity of the nervous system (White et al., 1986; Cook et al., 2019) and single-cell gene expression patterns across development (Taylor et al., 2021). These data are curated in publicly accessible databases such as WormAtlas (Altun et al., 2009) and CeNGEM (Caenorhabditis elegans Neuronal Gene Expression Network) (Taylor et al., 2021).
Gap junctions are specialized ion channels that facilitate electrical coupling between cells (Sohl et al., 2005). They are made up of innexin subunits (connexins in vertebrates), of which there are 25 in C. elegans (Starich et al., 1996; Simonsen et al., 2014). In this study, I analyse the expression of innexins in identified motor neurons and command interneurons. Specifically, I examine the spectrum of expressed innexins at coupled electrical synapses, where striking molecular asymmetries suggest these junctions function as rectifying diodes (Starich et al., 2009; Liu et al., 2020).
The expression maps of the 25 C. elegans innexins reveal two general patterns: generalized expression, such as unc-7 and unc-9 which are co-expressed across 69.9% of all neurons, and restricted expression, where certain innexins exhibit relatively high expression in small neuronal subsets, such as inx-21 and inx-22 which are uniquely expressed in SMD neurons (Taylor et al., 2021).
A generic gap junction is broadly considered a symmetrical structure that permits bidirectional passage of ions or small molecules between coupled cells (Sohl et al., 2005). However, functionally asymmetric electrical synapses have been described that preferentially permit current flow in one direction (Phelan et al., 2008; Starich et al., 2009; Liu et al., 2020). Such gap junctions are structurally asymmetric, most straightforwardly achieved by incorporating differing innexin subunits into the paired hemichannels of adjacent cells (Palacios-Prado et al., 2014).
Figure 1A details examples of molecular asymmetry in neural circuits associated with major motor neurons innervating body wall muscles (VA, VB) and head muscles (SMB, SMD). One prominent form of asymmetry involves the stoichiometric ratio of the widely expressed innexins unc-7 and unc-9. While the mean organism-wide unc-7/unc-9 ratio across co-expressing neurons is 1.60, major command interneurons AVA and AVB exhibit ratios of 6.15 and 5.65, respectively—nearly four times the neuronal baseline. Even more prominent innexin asymmetries are demonstrated by the restricted expression of inx-21 and inx-22 in SMD and eat-5 in SMB and SAA.
Strikingly, these asymmetrical gap junctions selectively involve circuitry tied to motor neurons driving body (VA, VB) and head (SMB, SMD) locomotion (Fig. 1B, C). All these motor neuron classes share the hallmark anatomical feature of extended, morphologically undifferentiated longitudinal processes situated distal to their neuromuscular output zones (Fig. 1D, E). It has long been posited that these distal extensions act as proprioceptors, transducing local body bending into downstream muscle activation during undulatory locomotion (White et al., 1986; Wen et al., 2012).
Rectifying gap junctions function effectively as blocking diodes that restrict ionic current flow to a single direction (Shui et al., 2020). For motor neurons possessing dual motor-proprioceptive modalities (VA, VB, SMB, SMD), diode rectification would be vital to prevent locally generated, stretch-activated electrical signals from back-propagating antidromically into critical central interneurons, such as the major network hub RIB (Fig. 1C). Supporting this hypothesis, major motor neurons lacking extended proprioceptive process extensions, such as RMD, exhibit no corresponding innexin asymmetries in their gap junctions.
Combining connectomic mapping with cell-specific transcriptomic profiling can provide key functional insights into neural circuitry. Such findings provide testable hypotheses to guide future electrophysiological experiments and computational modelling aimed at deciphering how a nervous system generates the behaviours that control an organism.
","references":[{"reference":"Brenner S. 1974. The genetics of Caenorhabditis elegans.","pubmedId":"","doi":"10.1093/genetics/77.1.71"},{"reference":"White JG, Southgate E, Thomson JN, Brenner S. 1986. The structure of the nervous system of the nematode Caenorhabditis elegans.","pubmedId":"","doi":"10.1098/rstb.1986.0056"},{"reference":"Starich TA, Lee RY, Panzarella C, Avery L, Shaw JE. 1996. eat-5 and unc-7 encode innexin gap junction proteins in Caenorhabditis elegans.","pubmedId":"","doi":"10.1083/jcb.134.2.537"},{"reference":"Sohl G, Maxeiner S, Willecke K. 2005. Expression and functions of neuronal gap junctions.","pubmedId":"","doi":"10.1038/nrn1627"},{"reference":"Phelan P, Goulding DA, Tam JL, Allen MJ, Curtin KD, Bacon JP. 2008. Molecular mechanism of rectification at an electrical synapse.","pubmedId":"","doi":"10.1016/j.cub.2008.02.073"},{"reference":"Altun ZF, Herndon LA, Wolkow CA, Crocker C, Lints R, Hall DH. 2009. WormAtlas.","pubmedId":"","doi":""},{"reference":"Starich TA, Xu J, Skerrett IM, Nicholson BJ, Shaw JE. 2009. Interactions between C. elegans innexins UNC-7 and UNC-9 in heterotypic electrical synapses.","pubmedId":"","doi":"10.1091/mbc.e09-03-0251"},{"reference":"Wen Q, Po MD, Hulme E, Patel S, Liu X, Greenwood M, Samuel AD. 2012. Proprioceptive coupling within motor neurons drives C. elegans locomotion.","pubmedId":"","doi":"10.1016/j.neuron.2012.08.039"},{"reference":"Palacios Prado N, Chapuis S, Panjkovich A, Freitas Andrade M, Naus CC, Bukauskas FF. 2014. Molecular determinants of voltage gating in innexin large-pore gap junction channels.","pubmedId":"","doi":"10.1016/j.bpj.2014.02.034"},{"reference":"Simonsen KT, Moerman DG, Naus CC. 2014. Gap junctions in C. elegans.","pubmedId":"","doi":"10.3389/fphys.2014.00040"},{"reference":"Cook SJ, Jarrell TA, Brittin CA, Wang Y, Bloniarz AE, Yakovlev MA, et al., Emmons SW. 2019. Whole-animal connectomes of both Caenorhabditis elegans sexes.","pubmedId":"","doi":"10.1038/s41586-019-1352-7"},{"reference":"Shui Y, Liu P, Chen B, Wang ZW. 2020. Molecular basis of junctional current rectification at an electrical synapse.","pubmedId":"","doi":"10.1126/sciadv.abb3076"},{"reference":"Taylor SR, Santpere G, Weinreb A, Barrett A, Sethi AK, Barkoulas M, Miller DM. 2021. Molecular topography of the adult Caenorhabditis elegans nervous system.","pubmedId":"","doi":"10.1016/j.cell.2021.06.023"},{"reference":"Goriely A. 2024. Eighty-six billion and counting: do we know the number of neurons in the human brain?.","pubmedId":"","doi":"10.1093/brain/awae390"},{"reference":"Brenner S. 1974. The genetics of Caenorhabditis elegans.","pubmedId":"","doi":"10.1093/genetics/77.1.71"},{"reference":"White JG, Southgate E, Thomson JN, Brenner S. 1986. The structure of the nervous system of the nematode Caenorhabditis elegans.","pubmedId":"","doi":"10.1098/rstb.1986.0056"},{"reference":"Starich TA, Lee RY, Panzarella C, Avery L, Shaw JE. 1996. eat-5 and unc-7 encode innexin gap junction proteins in Caenorhabditis elegans.","pubmedId":"","doi":"10.1083/jcb.134.2.537"},{"reference":"Sohl G, Maxeiner S, Willecke K. 2005. Expression and functions of neuronal gap junctions.","pubmedId":"","doi":"10.1038/nrn1627"},{"reference":"Phelan P, Goulding DA, Tam JL, Allen MJ, Curtin KD, Bacon JP. 2008. Molecular mechanism of rectification at an electrical synapse.","pubmedId":"","doi":"10.1016/j.cub.2008.02.073"},{"reference":"Altun ZF, Herndon LA, Wolkow CA, Crocker C, Lints R, Hall DH. 2009. WormAtlas.","pubmedId":"","doi":""},{"reference":"Starich TA, Xu J, Skerrett IM, Nicholson BJ, Shaw JE. 2009. Interactions between C. elegans innexins UNC-7 and UNC-9 in heterotypic electrical synapses.","pubmedId":"","doi":"10.1091/mbc.e09-03-0251"},{"reference":"Wen Q, Po MD, Hulme E, Patel S, Liu X, Greenwood M, Samuel AD. 2012. Proprioceptive coupling within motor neurons drives C. elegans locomotion.","pubmedId":"","doi":"10.1016/j.neuron.2012.08.039"},{"reference":"Palacios Prado N, Chapuis S, Panjkovich A, Freitas Andrade M, Naus CC, Bukauskas FF. 2014. Molecular determinants of voltage gating in innexin large-pore gap junction channels.","pubmedId":"","doi":"10.1016/j.bpj.2014.02.034"},{"reference":"Simonsen KT, Moerman DG, Naus CC. 2014. Gap junctions in C. elegans.","pubmedId":"","doi":"10.3389/fphys.2014.00040"},{"reference":"Cook SJ, Jarrell TA, Brittin CA, Wang Y, Bloniarz AE, Yakovlev MA, et al., Emmons SW. 2019. Whole-animal connectomes of both Caenorhabditis elegans sexes.","pubmedId":"","doi":"10.1038/s41586-019-1352-7"},{"reference":"Shui Y, Liu P, Chen B, Wang ZW. 2020. Molecular basis of junctional current rectification at an electrical synapse.","pubmedId":"","doi":"10.1126/sciadv.abb3076"},{"reference":"Taylor SR, Santpere G, Weinreb A, Barrett A, Sethi AK, Barkoulas M, Miller DM. 2021. Molecular topography of the adult Caenorhabditis elegans nervous system.","pubmedId":"","doi":"10.1016/j.cell.2021.06.023"},{"reference":"Goriely A. 2024. Eighty-six billion and counting: do we know the number of neurons in the human brain?.","pubmedId":"","doi":"10.1093/brain/awae390"}],"title":"Gap junction innexin asymmetry in C.
elegans suggests a diode blocking
mechanism to prevent antidromic backpropagation
from motor neurons to
command interneurons
","reviews":[],"curatorReviews":[{"curator":{"displayName":"Gary Craig Schindelman"},"openAcknowledgement":false,"submitted":null}]},{"id":"8944e9e5-fa44-4e33-8d1f-f7b1b7b95ee0","decision":"edit","abstract":"The availability of single-cell transcriptomes and electron-microscopy connectomes in Caenorhabditis elegans facilitates detailed perusal of expressed genes in every neuron of its nervous system. In this report, I describe striking asymmetric arrangements of gap junction proteins (innexins) forming electrical synapses between command interneurons (AVA, AVB, RIB) and downstream motor neurons (VA, VB, SMB, SMD). A key feature of these motor neurons is the presence of long, morphologically undifferentiated process regions situated distally from neuromuscular junctions, hypothesized to function as proprioceptive stretch receptors. The stoichiometric asymmetry and selective expression of putative rectifying innexins (including unc-7, unc-9, eat-5, inx-19, and inx-21/22) at these electrical synapses suggest that these junctions act as rectifying diodes. Such an arrangement would prevent locally generated antidromic action potentials or self-stimulated motor activity from backpropagating into central command interneurons.
","acknowledgements":"","authors":[{"affiliations":["University of Wisconsin–Madison, Madison, WI, United States"],"departments":["Emeritus Professor"],"credit":["conceptualization","formalAnalysis","writing_originalDraft"],"email":"kc9fyh@gmail.com","firstName":"John","lastName":"White","submittingAuthor":true,"correspondingAuthor":true,"equalContribution":false,"WBId":null,"orcid":null}],"awards":[],"conflictsOfInterest":"The authors declare that there are no conflicts of interest present.
","dataTable":{"url":null},"extendedData":[],"funding":"No funding used
","image":{"url":"https://portal.micropublication.org/uploads/d16cda41f9b86b7f38e8e4e38fd7c0d5.png"},"imageCaption":"Expression asymmetry of gap junction innexins suggests a rectifying diode isolation mechanism between command interneurons and motor circuit processes.
(A) Innexin expression matrix in identified neurons. Single-cell RNA-seq expression levels (mean TPM, CeNGEN adult dataset; Taylor et al., 2021) of innexins (unc-7, unc-9, inx-21, inx-22, eat-5, and inx-19) in head motor neurons (SMB, SMD), body motor neurons (VA, VB), and associated interneurons (AVA, AVB, RIB, SAA). Bold values highlight dominant expression or key asymmetrical ratios. Note the pronounced unc-7/unc-9 expression ratio skew toward command interneurons (AVA: 6.15; AVB: 5.65; SAA: 3.87). The mean unc-7/unc-9 ratio for all co-expressing neurons in the organism is 1.60. AVB exhibits a high unc-7/unc-9 ratio together with selective expression of the asymmetric innexin inx-19. SAA also exhibits a high unc-7/unc-9 ratio together with selective expression of the asymmetric innexin eat-5. (B) Putative electrical synapses in body motor neuron circuitry. Schematic representation of asymmetric gap junctions between command interneurons (AVA, AVB) and ventral cord motor neurons (VA, VB). Heterotypic coupling between UNC-7 (interneuron side) and UNC-9 (motor neuron side), as well as selective INX-19 expression in AVB, suggests the presence of functional electrical diodes (indicated by diode symbols) configured to pass depolarizing current anterograde while blocking antidromic back-propagation (Starich et al., 2009; Liu et al., 2020). Green bars indicate the presence of distal, uninnervated process extensions hypothesized to function as proprioceptive stretch receptors (White et al., 1986; Wen et al., 2012). AVA also makes chemical synapses onto VA motor neurons (indicated by arrow). (C) Putative electrical synapses in head motor neuron circuitry. Circuit diagram showing asymmetrical gap junctions between head motor neurons (SMB, SMD) and head interneurons (RIB, SAA). EAT-5 is selectively expressed in SMB and SAA, while both INX-21 and INX-22 are selectively expressed in SMD, establishing distinct asymmetric electrical coupling in head motor neuron circuitry (Starich et al., 1996; Simonsen et al., 2014). RIB is a major hub interneuron of the central nervous system (White et al., 1986; Cook et al., 2019). The rectifying electrical connections to SMB and SMD act to isolate RIB from the back-propagation of local electrical activity produced by the proprioceptive activation of SMB and SMD. SAA makes a chemical synapse (arrow) onto SMD in addition to its electrical connection to SMB. (D) Process morphology of body motor neurons VA3 and VB4. Anatomical schematics depicting the extended, morphologically undifferentiated distal processes (green) of VA3 and VB4 extending beyond neuromuscular junction zones (red bars). (E) Process morphology of dorsal head motor neurons SMBDL and SMDDL. Anatomical schematics illustrating the process trajectories of SMBDL and SMDDL, highlighting distal sensory/proprioceptive extensions (green) relative to synaptic output regions within the nerve ring (red). These processes run down the length of the body in small sub-lateral cords. Cell bodies are shown in black. Panels (D) and (E) adapted from White et al. (1986).
","imageTitle":"Innexin asymmetries in motor neuron circuitry
","methods":"Transcriptomic and Connectomic Data Analysis
Single-cell RNA sequencing expression levels (Transcripts Per Million, TPM) for all 25 Caenorhabditis elegans innexins across 133 identified neuronal cell types were extracted from the adult CeNGEN dataset (Taylor et al., 2021). Co-expression frequencies and mean expression ratios were calculated using custom Python scripts running in Google Colab (Python 3.10; pandas v2.0, numpy v1.24). Neuronal co-expression of unc-7 and unc-9 was defined as non-zero TPM values (>0.0 TPM) in both genes across the 133 annotated neuron classes. Anatomical connectivity, chemical and electrical synapse counts, and motor neuron process morphologies were cross-referenced against the EM connectome datasets (White et al., 1986; Cook et al., 2019) and WormAtlas (Altun et al., 2009).
Computational Collaboration & AI Support
Large Language Model AI assistance (Gemini, Google) was utilized as a collaborative tool during manuscript preparation. Specifically, AI code execution environments were employed to write and run Python scripts for dataset parsing, co-expression statistics calculations, and matrix formatting. The AI was also used to assist with composite figure layout montaging (via matplotlib and PIL), reference formatting, and editorial polishing of text drafts under direct author supervision.
","reagents":"","patternDescription":"The nervous system of C. elegans comprises a total complement of only 302 neurons, yet contains the foundational circuit principles of vertebrate nervous systems, which, in humans, contain about 86 billion neurons (Goriely, 2024). In the mid-1960s, Sydney Brenner pioneered the use of C. elegans as a genetic model system to dissect nervous system development and function (Brenner, 1974). Since then, extensive research has generated comprehensive datasets detailing both the structural connectivity of the nervous system (White et al., 1986; Cook et al., 2019) and single-cell gene expression patterns across development (Taylor et al., 2021). These data are curated in publicly accessible databases such as WormAtlas (Altun et al., 2009) and CeNGEM (Caenorhabditis elegans Neuronal Gene Expression Network) (Taylor et al., 2021).
Gap junctions are specialized ion channels that facilitate electrical coupling between cells (Sohl et al., 2005). They are made up of innexin subunits (connexins in vertebrates), of which there are 25 in C. elegans (Starich et al., 1996; Simonsen et al., 2014). In this study, I analyse the expression of innexins in identified motor neurons and command interneurons. Specifically, I examine the spectrum of expressed innexins at coupled electrical synapses, where striking molecular asymmetries suggest these junctions function as rectifying diodes (Starich et al., 2009; Liu et al., 2020).
The expression maps of the 25 C. elegans innexins reveal two general patterns: generalized expression, such as unc-7 and unc-9 which are co-expressed across 69.9% of all neurons, and restricted expression, where certain innexins exhibit relatively high expression in small neuronal subsets, such as inx-21 and inx-22 which are uniquely expressed in SMD neurons (Taylor et al., 2021).
A generic gap junction is broadly considered a symmetrical structure that permits bidirectional passage of ions or small molecules between coupled cells (Sohl et al., 2005). However, functionally asymmetric electrical synapses have been described that preferentially permit current flow in one direction (Phelan et al., 2008; Starich et al., 2009; Liu et al., 2020). Such gap junctions are structurally asymmetric, most straightforwardly achieved by incorporating differing innexin subunits into the paired hemichannels of adjacent cells (Palacios-Prado et al., 2014).
Figure 1A details examples of molecular asymmetry in neural circuits associated with major motor neurons innervating body wall muscles (VA, VB) and head muscles (SMB, SMD). One prominent form of asymmetry involves the stoichiometric ratio of the widely expressed innexins unc-7 and unc-9. While the mean organism-wide unc-7/unc-9 ratio across co-expressing neurons is 1.60, major command interneurons AVA and AVB exhibit ratios of 6.15 and 5.65, respectively—nearly four times the neuronal baseline. Even more prominent innexin asymmetries are demonstrated by the restricted expression of inx-21 and inx-22 in SMD and eat-5 in SMB and SAA.
Strikingly, these asymmetrical gap junctions selectively involve circuitry tied to motor neurons driving body (VA, VB) and head (SMB, SMD) locomotion (Fig. 1B, C). All these motor neuron classes share the hallmark anatomical feature of extended, morphologically undifferentiated longitudinal processes situated distal to their neuromuscular output zones (Fig. 1D, E). It has long been posited that these distal extensions act as proprioceptors, transducing local body bending into downstream muscle activation during undulatory locomotion (White et al., 1986; Wen et al., 2012).
Rectifying gap junctions function effectively as blocking diodes that restrict ionic current flow to a single direction (Shui et al., 2020). For motor neurons possessing dual motor-proprioceptive modalities (VA, VB, SMB, SMD), diode rectification would be vital to prevent locally generated, stretch-activated electrical signals from back-propagating antidromically into critical central interneurons, such as the major network hub RIB (Fig. 1C). Supporting this hypothesis, major motor neurons lacking extended proprioceptive process extensions, such as RMD, exhibit no corresponding innexin asymmetries in their gap junctions.
Combining connectomic mapping with cell-specific transcriptomic profiling can provide key functional insights into neural circuitry. Such findings provide testable hypotheses to guide future electrophysiological experiments and computational modelling aimed at deciphering how a nervous system generates the behaviours that control an organism.
","references":[{"reference":"Altun ZF, Herndon LA, Wolkow CA, Crocker C, Lints R, Hall DH. 2009. WormAtlas.","pubmedId":"","doi":""},{"reference":"Brenner S. 1974. The genetics of Caenorhabditis elegans.","pubmedId":"","doi":"10.1093/genetics/77.1.71"},{"reference":"Cook SJ, Jarrell TA, Brittin CA, Wang Y, Bloniarz AE, Yakovlev MA, et al., Emmons SW. 2019. Whole-animal connectomes of both Caenorhabditis elegans sexes.","pubmedId":"","doi":"10.1038/s41586-019-1352-7"},{"reference":"Goriely A. 2024. Eighty-six billion and counting: do we know the number of neurons in the human brain?.","pubmedId":"","doi":"10.1093/brain/awae390"},{"reference":"Palacios Prado N, Chapuis S, Panjkovich A, Freitas Andrade M, Naus CC, Bukauskas FF. 2014. Molecular determinants of voltage gating in innexin large-pore gap junction channels.","pubmedId":"","doi":"10.1016/j.bpj.2014.02.034"},{"reference":"Phelan P, Goulding DA, Tam JL, Allen MJ, Curtin KD, Bacon JP. 2008. Molecular mechanism of rectification at an electrical synapse.","pubmedId":"","doi":"10.1016/j.cub.2008.02.073"},{"reference":"Shui Y, Liu P, Chen B, Wang ZW. 2020. Molecular basis of junctional current rectification at an electrical synapse.","pubmedId":"","doi":"10.1126/sciadv.abb3076"},{"reference":"Simonsen KT, Moerman DG, Naus CC. 2014. Gap junctions in C. elegans.","pubmedId":"","doi":"10.3389/fphys.2014.00040"},{"reference":"Sohl G, Maxeiner S, Willecke K. 2005. Expression and functions of neuronal gap junctions.","pubmedId":"","doi":"10.1038/nrn1627"},{"reference":"Starich TA, Lee RY, Panzarella C, Avery L, Shaw JE. 1996. eat-5 and unc-7 encode innexin gap junction proteins in Caenorhabditis elegans.","pubmedId":"","doi":"10.1083/jcb.134.2.537"},{"reference":"Starich TA, Xu J, Skerrett IM, Nicholson BJ, Shaw JE. 2009. Interactions between C. elegans innexins UNC-7 and UNC-9 in heterotypic electrical synapses.","pubmedId":"","doi":"10.1091/mbc.e09-03-0251"},{"reference":"Taylor SR, Santpere G, Weinreb A, Barrett A, Sethi AK, Barkoulas M, Miller DM. 2021. Molecular topography of the adult Caenorhabditis elegans nervous system.","pubmedId":"","doi":"10.1016/j.cell.2021.06.023"},{"reference":"Wen Q, Po MD, Hulme E, Patel S, Liu X, Greenwood M, Samuel AD. 2012. Proprioceptive coupling within motor neurons drives C. elegans locomotion.","pubmedId":"","doi":"10.1016/j.neuron.2012.08.039"},{"reference":"White JG, Southgate E, Thomson JN, Brenner S. 1986. The structure of the nervous system of the nematode Caenorhabditis elegans.","pubmedId":"","doi":"10.1098/rstb.1986.0056"}],"title":"Gap junction innexin asymmetry in C. elegans suggests a diode blocking mechanism to prevent antidromic backpropagation from motor neurons to command interneurons","reviews":[{"reviewer":{"displayName":"Scott Emmons"},"openAcknowledgement":true,"status":{"submitted":true}}],"curatorReviews":[{"curator":{"displayName":"Gary Craig Schindelman"},"openAcknowledgement":false,"submitted":null}]},{"id":"89fac1a6-b791-46f1-80db-b36ffb098a81","decision":"revise","abstract":"The availability of single-cell transcriptomes and electron-microscopy connectomes in Caenorhabditis elegans facilitates detailed perusal of expressed genes in every neuron of its nervous system. In this report, I describe striking asymmetric arrangements of gap junction proteins (innexins) forming electrical synapses between command interneurons (AVA, AVB, RIB) and downstream motor neurons (VA, VB, SMB, SMD). A key feature of these motor neurons is the presence of long, morphologically undifferentiated process regions situated distally from neuromuscular junctions, hypothesized to function as proprioceptive stretch receptors. The stoichiometric asymmetry and selective expression of putative rectifying innexins (including unc-7, unc-9, eat-5, inx-19, and inx-21/22) at these electrical synapses suggest that these junctions act as rectifying diodes. Such an arrangement would prevent locally generated antidromic action potentials or self-stimulated motor activity from backpropagating into central command interneurons.
","acknowledgements":"","authors":[{"affiliations":["University of Wisconsin–Madison, Madison, WI, United States"],"departments":["Emeritus Professor"],"credit":["conceptualization","formalAnalysis","writing_originalDraft"],"email":"kc9fyh@gmail.com","firstName":"John","lastName":"White","submittingAuthor":true,"correspondingAuthor":true,"equalContribution":false,"WBId":null,"orcid":null}],"awards":[],"conflictsOfInterest":"The authors declare that there are no conflicts of interest present.
","dataTable":{"url":null},"extendedData":[],"funding":"No funding used
","image":{"url":"https://portal.micropublication.org/uploads/d16cda41f9b86b7f38e8e4e38fd7c0d5.png"},"imageCaption":"Expression asymmetry of gap junction innexins suggests a rectifying diode isolation mechanism between command interneurons and motor circuit processes.
(A) Innexin expression matrix in identified neurons. Single-cell RNA-seq expression levels (mean TPM, CeNGEN adult dataset; Taylor et al., 2021) of innexins (unc-7, unc-9, inx-21, inx-22, eat-5, and inx-19) in head motor neurons (SMB, SMD), body motor neurons (VA, VB), and associated interneurons (AVA, AVB, RIB, SAA). Bold values highlight dominant expression or key asymmetrical ratios. Note the pronounced unc-7/unc-9 expression ratio skew toward command interneurons (AVA: 6.15; AVB: 5.65; SAA: 3.87). The mean unc-7/unc-9 ratio for all co-expressing neurons in the organism is 1.60. AVB exhibits a high unc-7/unc-9 ratio together with selective expression of the asymmetric innexin inx-19. SAA also exhibits a high unc-7/unc-9 ratio together with selective expression of the asymmetric innexin eat-5. (B) Putative electrical synapses in body motor neuron circuitry. Schematic representation of asymmetric gap junctions between command interneurons (AVA, AVB) and ventral cord motor neurons (VA, VB). Heterotypic coupling between UNC-7 (interneuron side) and UNC-9 (motor neuron side), as well as selective INX-19 expression in AVB, suggests the presence of functional electrical diodes (indicated by diode symbols) configured to pass depolarizing current anterograde while blocking antidromic back-propagation (Starich et al., 2009; Liu et al., 2020). Green bars indicate the presence of distal, uninnervated process extensions hypothesized to function as proprioceptive stretch receptors (White et al., 1986; Wen et al., 2012). AVA also makes chemical synapses onto VA motor neurons (indicated by arrow). (C) Putative electrical synapses in head motor neuron circuitry. Circuit diagram showing asymmetrical gap junctions between head motor neurons (SMB, SMD) and head interneurons (RIB, SAA). EAT-5 is selectively expressed in SMB and SAA, while both INX-21 and INX-22 are selectively expressed in SMD, establishing distinct asymmetric electrical coupling in head motor neuron circuitry (Starich et al., 1996; Simonsen et al., 2014). RIB is a major hub interneuron of the central nervous system (White et al., 1986; Cook et al., 2019). The rectifying electrical connections to SMB and SMD act to isolate RIB from the back-propagation of local electrical activity produced by the proprioceptive activation of SMB and SMD. SAA makes a chemical synapse (arrow) onto SMD in addition to its electrical connection to SMB. (D) Process morphology of body motor neurons VA3 and VB4. Anatomical schematics depicting the extended, morphologically undifferentiated distal processes (green) of VA3 and VB4 extending beyond neuromuscular junction zones (red bars). (E) Process morphology of dorsal head motor neurons SMBDL and SMDDL. Anatomical schematics illustrating the process trajectories of SMBDL and SMDDL, highlighting distal sensory/proprioceptive extensions (green) relative to synaptic output regions within the nerve ring (red). These processes run down the length of the body in small sub-lateral cords. Cell bodies are shown in black. Panels (D) and (E) adapted from White et al. (1986).
","imageTitle":"Innexin asymmetries in motor neuron circuitry
","methods":"Transcriptomic and Connectomic Data Analysis
Single-cell RNA sequencing expression levels (Transcripts Per Million, TPM) for all 25 Caenorhabditis elegans innexins across 133 identified neuronal cell types were extracted from the adult CeNGEN dataset (Taylor et al., 2021). Co-expression frequencies and mean expression ratios were calculated using custom Python scripts running in Google Colab (Python 3.10; pandas v2.0, numpy v1.24). Neuronal co-expression of unc-7 and unc-9 was defined as non-zero TPM values (>0.0 TPM) in both genes across the 133 annotated neuron classes. Anatomical connectivity, chemical and electrical synapse counts, and motor neuron process morphologies were cross-referenced against the EM connectome datasets (White et al., 1986; Cook et al., 2019) and WormAtlas (Altun et al., 2009).
","reagents":"","patternDescription":"The nervous system of C. elegans comprises a total complement of only 302 neurons, yet contains the foundational circuit principles of vertebrate nervous systems, which, in humans, contain about 86 billion neurons (Goriely, 2024). In the mid-1960s, Sydney Brenner pioneered the use of C. elegans as a genetic model system to dissect nervous system development and function (Brenner, 1974). Since then, extensive research has generated comprehensive datasets detailing both the structural connectivity of the nervous system (White et al., 1986; Cook et al., 2019) and single-cell gene expression patterns across development (Taylor et al., 2021). These data are curated in publicly accessible databases such as WormAtlas (Altun et al., 2009) and CeNGEM (Caenorhabditis elegans Neuronal Gene Expression Network) (Taylor et al., 2021).
Gap junctions are specialized ion channels that facilitate electrical coupling between cells (Sohl et al., 2005). They are made up of innexin subunits (connexins in vertebrates), of which there are 25 in C. elegans (Starich et al., 1996; Simonsen et al., 2014). In this study, I analyse the expression of innexins in identified motor neurons and command interneurons. Specifically, I examine the spectrum of expressed innexins at coupled electrical synapses, where striking molecular asymmetries suggest these junctions function as rectifying diodes (Starich et al., 2009; Liu et al., 2020).
The expression maps of the 25 C. elegans innexins reveal two general patterns: generalized expression, such as unc-7 and unc-9 which are co-expressed across 69.9% of all neurons, and restricted expression, where certain innexins exhibit relatively high expression in small neuronal subsets, such as inx-21 and inx-22 which are uniquely expressed in SMD neurons (Taylor et al., 2021).
A generic gap junction is broadly considered a symmetrical structure that permits bidirectional passage of ions or small molecules between coupled cells (Sohl et al., 2005). However, functionally asymmetric electrical synapses have been described that preferentially permit current flow in one direction (Phelan et al., 2008; Starich et al., 2009; Liu et al., 2020). Such gap junctions are structurally asymmetric, most straightforwardly achieved by incorporating differing innexin subunits into the paired hemichannels of adjacent cells (Palacios-Prado et al., 2014).
Figure 1A details examples of molecular asymmetry in neural circuits associated with major motor neurons innervating body wall muscles (VA, VB) and head muscles (SMB, SMD). One prominent form of asymmetry involves the stoichiometric ratio of the widely expressed innexins unc-7 and unc-9. While the mean organism-wide unc-7/unc-9 ratio across co-expressing neurons is 1.60, major command interneurons AVA and AVB exhibit ratios of 6.15 and 5.65, respectively—nearly four times the neuronal baseline. Even more prominent innexin asymmetries are demonstrated by the restricted expression of inx-21 and inx-22 in SMD and eat-5 in SMB and SAA.
Strikingly, these asymmetrical gap junctions selectively involve circuitry tied to motor neurons driving body (VA, VB) and head (SMB, SMD) locomotion (Fig. 1B, C). All these motor neuron classes share the hallmark anatomical feature of extended, morphologically undifferentiated longitudinal processes situated distal to their neuromuscular output zones (Fig. 1D, E). It has long been posited that these distal extensions act as proprioceptors, transducing local body bending into downstream muscle activation during undulatory locomotion (White et al., 1986; Wen et al., 2012).
Rectifying gap junctions function effectively as blocking diodes that restrict ionic current flow to a single direction (Shui et al., 2020). For motor neurons possessing dual motor-proprioceptive modalities (VA, VB, SMB, SMD), diode rectification would be vital to prevent locally generated, stretch-activated electrical signals from back-propagating antidromically into critical central interneurons, such as the major network hub RIB (Fig. 1C). Supporting this hypothesis, major motor neurons lacking extended proprioceptive process extensions, such as RMD, exhibit no corresponding innexin asymmetries in their gap junctions.
Combining connectomic mapping with cell-specific transcriptomic profiling can provide key functional insights into neural circuitry. Such findings provide testable hypotheses to guide future electrophysiological experiments and computational modelling aimed at deciphering how a nervous system generates the behaviours that control an organism.
","references":[{"reference":"Altun ZF, Herndon LA, Wolkow CA, Crocker C, Lints R, Hall DH. 2009. WormAtlas.","pubmedId":"","doi":""},{"reference":"Brenner S. 1974. The genetics of Caenorhabditis elegans.","pubmedId":"","doi":"10.1093/genetics/77.1.71"},{"reference":"Cook SJ, Jarrell TA, Brittin CA, Wang Y, Bloniarz AE, Yakovlev MA, et al., Emmons SW. 2019. Whole-animal connectomes of both Caenorhabditis elegans sexes.","pubmedId":"","doi":"10.1038/s41586-019-1352-7"},{"reference":"Goriely A. 2024. Eighty-six billion and counting: do we know the number of neurons in the human brain?.","pubmedId":"","doi":"10.1093/brain/awae390"},{"reference":"Palacios Prado N, Chapuis S, Panjkovich A, Freitas Andrade M, Naus CC, Bukauskas FF. 2014. Molecular determinants of voltage gating in innexin large-pore gap junction channels.","pubmedId":"","doi":"10.1016/j.bpj.2014.02.034"},{"reference":"Phelan P, Goulding DA, Tam JL, Allen MJ, Curtin KD, Bacon JP. 2008. Molecular mechanism of rectification at an electrical synapse.","pubmedId":"","doi":"10.1016/j.cub.2008.02.073"},{"reference":"Shui Y, Liu P, Chen B, Wang ZW. 2020. Molecular basis of junctional current rectification at an electrical synapse.","pubmedId":"","doi":"10.1126/sciadv.abb3076"},{"reference":"Simonsen KT, Moerman DG, Naus CC. 2014. Gap junctions in C. elegans.","pubmedId":"","doi":"10.3389/fphys.2014.00040"},{"reference":"Sohl G, Maxeiner S, Willecke K. 2005. Expression and functions of neuronal gap junctions.","pubmedId":"","doi":"10.1038/nrn1627"},{"reference":"Starich TA, Lee RY, Panzarella C, Avery L, Shaw JE. 1996. eat-5 and unc-7 encode innexin gap junction proteins in Caenorhabditis elegans.","pubmedId":"","doi":"10.1083/jcb.134.2.537"},{"reference":"Starich TA, Xu J, Skerrett IM, Nicholson BJ, Shaw JE. 2009. Interactions between C. elegans innexins UNC-7 and UNC-9 in heterotypic electrical synapses.","pubmedId":"","doi":"10.1091/mbc.e09-03-0251"},{"reference":"Taylor SR, Santpere G, Weinreb A, Barrett A, Sethi AK, Barkoulas M, Miller DM. 2021. Molecular topography of the adult Caenorhabditis elegans nervous system.","pubmedId":"","doi":"10.1016/j.cell.2021.06.023"},{"reference":"Wen Q, Po MD, Hulme E, Patel S, Liu X, Greenwood M, Samuel AD. 2012. Proprioceptive coupling within motor neurons drives C. elegans locomotion.","pubmedId":"","doi":"10.1016/j.neuron.2012.08.039"},{"reference":"White JG, Southgate E, Thomson JN, Brenner S. 1986. The structure of the nervous system of the nematode Caenorhabditis elegans.","pubmedId":"","doi":"10.1098/rstb.1986.0056"}],"title":"Gap junction innexin asymmetry in C. elegans suggests a diode blocking mechanism to prevent antidromic backpropagation from motor neurons to command interneurons","reviews":[],"curatorReviews":[{"curator":{"displayName":"Gary Craig Schindelman"},"openAcknowledgement":false,"submitted":null}]},{"id":"245783e7-034c-4f2a-97d4-a2889e08a399","decision":"edit","abstract":"In C. elegans, gap junctions between command interneurons and motor neurons mediate rapid behavioural transitions. However, antidromic backpropagation driven by the putative proprioceptive activity of motor neurons with Extended Longitudinal Neurites (ELNs) must be blocked to maintain circuit directionality. Analysing single-cell transcriptomics (CeNGEN), I identify systematic innexin gene expression asymmetry across major motor circuit electrical synapses. Presynaptic interneurons and postsynaptic motor neurons express distinct, non-overlapping innexin subunits. This molecular asymmetry suggests a rectified, diode-like gating mechanism that favours orthodromic signalling while preventing antidromic backpropagation from proprioceptive motor neurons, providing a structural framework for directional electrical transmission.
","acknowledgements":"","authors":[{"affiliations":["University of Wisconsin–Madison, Madison, WI, United States"],"departments":["Emeritus Professor"],"credit":["conceptualization","formalAnalysis","writing_originalDraft"],"email":"kc9fyh@gmail.com","firstName":"John","lastName":"White","submittingAuthor":true,"correspondingAuthor":true,"equalContribution":false,"WBId":null,"orcid":null}],"awards":[],"conflictsOfInterest":"The authors declare that there are no conflicts of interest present.
","dataTable":{"url":null},"extendedData":[],"funding":"No funding used
","image":{"url":"https://portal.micropublication.org/uploads/d16cda41f9b86b7f38e8e4e38fd7c0d5.png"},"imageCaption":"Expression asymmetry of gap junction innexins suggests a rectifying diode isolation mechanism between command interneurons and motor circuit processes.
(A) Innexin expression matrix in identified neurons. Single-cell RNA-seq expression levels (mean TPM, CeNGEN adult dataset; Taylor et al., 2021) of innexins (unc-7, unc-9, inx-21, inx-22, eat-5, and inx-19) in head motor neurons (SMB, SMD), body motor neurons (VA, VB), and associated interneurons (AVA, AVB, RIB, SAA). Bold values highlight dominant expression or key asymmetrical ratios. Note the pronounced unc-7/unc-9 expression ratio skew toward command interneurons (AVA: 6.15; AVB: 5.65; SAA: 3.87). The mean unc-7/unc-9 ratio for all co-expressing neurons in the organism is 1.60. AVB exhibits a high unc-7/unc-9 ratio together with selective expression of the asymmetric innexin inx-19. SAA also exhibits a high unc-7/unc-9 ratio together with selective expression of the asymmetric innexin eat-5. (B) Putative electrical synapses in body motor neuron circuitry. Schematic representation of asymmetric gap junctions between command interneurons (AVA, AVB) and ventral cord motor neurons (VA, VB). Heterotypic coupling between UNC-7 (interneuron side) and UNC-9 (motor neuron side), as well as selective INX-19 expression in AVB, suggests the presence of functional electrical diodes (indicated by diode symbols) configured to pass depolarizing current anterograde while blocking antidromic back-propagation (Starich et al., 2009; Liu et al., 2020). Green bars indicate the presence of distal, uninnervated process extensions hypothesized to function as proprioceptive stretch receptors (White et al., 1986; Wen et al., 2012). AVA also makes chemical synapses onto VA motor neurons (indicated by arrow). (C) Putative electrical synapses in head motor neuron circuitry. Circuit diagram showing asymmetrical gap junctions between head motor neurons (SMB, SMD) and head interneurons (RIB, SAA). EAT-5 is selectively expressed in SMB and SAA, while both INX-21 and INX-22 are selectively expressed in SMD, establishing distinct asymmetric electrical coupling in head motor neuron circuitry (Starich et al., 1996; Simonsen et al., 2014). RIB is a major hub interneuron of the central nervous system (White et al., 1986; Cook et al., 2019). The rectifying electrical connections to SMB and SMD act to isolate RIB from the back-propagation of local electrical activity produced by the proprioceptive activation of SMB and SMD. SAA makes a chemical synapse (arrow) onto SMD in addition to its electrical connection to SMB. (D) Process morphology of body motor neurons VA3 and VB4. Anatomical schematics depicting the extended, morphologically undifferentiated distal processes (green) of VA3 and VB4 extending beyond neuromuscular junction zones (red bars). (E) Process morphology of dorsal head motor neurons SMBDL and SMDDL. Anatomical schematics illustrating the process trajectories of SMBDL and SMDDL, highlighting distal sensory/proprioceptive extensions (green) relative to synaptic output regions within the nerve ring (red). These processes run down the length of the body in small sub-lateral cords. Cell bodies are shown in black. Panels (D) and (E) adapted from White et al. (1986).
","imageTitle":"Innexin asymmetries in motor neuron circuitry
","methods":"Transcriptomic and Connectomic Data Analysis
Single-cell RNA sequencing expression levels (Transcripts Per Million, TPM) for all 25 Caenorhabditis elegans innexins across 133 identified neuronal cell types were extracted from the adult CeNGEN dataset (Taylor et al., 2021). Co-expression frequencies and mean expression ratios were calculated using custom Python scripts running in Google Colab (Python 3.10; pandas v2.0, numpy v1.24). Neuronal co-expression of unc-7 and unc-9 was defined as non-zero TPM values (>0.0 TPM) in both genes across the 133 annotated neuron classes. Anatomical connectivity, chemical and electrical synapse counts, and motor neuron process morphologies were cross-referenced against the EM connectome datasets (White et al., 1986; Cook et al., 2019) and WormAtlas (Altun et al., 2009).
","reagents":"","patternDescription":"The nervous system of C. elegans comprises a total complement of only 302 neurons, yet contains the foundational circuit principles of vertebrate nervous systems, which, in humans, contain about 86 billion neurons (Goriely, 2024). In the mid-1960s, Sydney Brenner pioneered the use of C. elegans as a genetic model system to dissect nervous system development and function (Brenner, 1974). Since then, extensive research has generated comprehensive datasets detailing both the structural connectivity of the nervous system (White et al., 1986; Cook et al., 2019) and single-cell gene expression patterns across development (Taylor et al., 2021). These data are curated in publicly accessible databases such as WormAtlas (Altun et al., 2009) and CeNGEN (Caenorhabditis elegans Neuronal Gene Expression Network) (Taylor et al., 2021).
Gap junctions are specialized ion channels that facilitate electrical coupling between cells (Sohl et al., 2005). They are made up of innexin subunits (connexins in vertebrates), of which there are 25 in C. elegans (Starich et al., 1996; Simonsen et al., 2014). In this study, I analyse the expression of innexins in identified motor neurons and command interneurons. Specifically, I examine the spectrum of expressed innexins at coupled electrical synapses, where striking molecular asymmetries suggest these junctions function as rectifying diodes (Starich et al., 2009; Liu et al., 2020).
The expression maps of the 25 C. elegans innexins reveal two general patterns: generalized expression, such as unc-7 and unc-9 which are co-expressed across 69.9% of all neurons, and restricted expression, where certain innexins exhibit relatively high expression in small neuronal subsets, such as inx-21 and inx-22 which are uniquely expressed in SMD neurons (Taylor et al., 2021).
A generic gap junction is broadly considered a symmetrical structure that permits bidirectional passage of ions or small molecules between coupled cells (Sohl et al., 2005). However, functionally asymmetric electrical synapses have been described that preferentially permit current flow in one direction (Phelan et al., 2008; Starich et al., 2009; Liu et al., 2020). Such gap junctions are structurally asymmetric, most straightforwardly achieved by incorporating differing innexin subunits into the paired hemichannels of adjacent cells (Palacios-Prado et al., 2014).
Figure 1A details examples of molecular asymmetry in neural circuits associated with major motor neurons innervating body wall muscles (VA, VB) and head muscles (SMB, SMD). These classes of neuron all have Extended Longitudinal Neurites (ELNs). One prominent form of asymmetry involves the stoichiometric ratio of the widely expressed innexins unc-7 and unc-9. While the mean organism-wide unc-7/unc-9 ratio across co-expressing neurons is 1.60, major command interneurons AVA and AVB exhibit ratios of 6.15 and 5.65, respectively—nearly four times the neuronal baseline. Even more prominent innexin asymmetries are demonstrated by the restricted expression of inx-21 and inx-22 in SMD and eat-5 in SMB and SAA.
Strikingly, these asymmetrical gap junctions selectively involve circuitry tied to motor neurons driving body (VA, VB) and head (SMB, SMD) locomotion (Fig. 1B, C). All these motor neuron classes share the hallmark anatomical feature of ELNs: morphologically undifferentiated longitudinal processes situated distal to their neuromuscular output zones (Fig. 1D, E). It has long been posited that these distal extensions act as proprioceptors, transducing local body bending into downstream muscle activation during undulatory locomotion (White et al., 1986; Wen et al., 2012).
Rectifying gap junctions function effectively as blocking diodes that restrict ionic current flow to a single direction (Shui et al., 2020). For motor neurons possessing dual motor-proprioceptive modalities (VA, VB, SMB, SMD), diode rectification would be vital to prevent locally generated, stretch-activated electrical signals from back-propagating antidromically into critical central interneurons, such as the major network hub RIB (Fig. 1C). Supporting this hypothesis, major motor neurons lacking extended proprioceptive process extensions, such as RMD, exhibit no corresponding innexin asymmetries in their gap junctions.
Combining connectomic mapping with cell-specific transcriptomic profiling can provide key functional insights into neural circuitry. Such findings provide testable hypotheses to guide future electrophysiological experiments and computational modelling aimed at deciphering how a nervous system generates the behaviours that control an organism.
","references":[{"reference":"Altun ZF, Herndon LA, Wolkow CA, Crocker C, Lints R, Hall DH. 2009. WormAtlas.","pubmedId":"","doi":""},{"reference":"Brenner S. 1974. The genetics of Caenorhabditis elegans.","pubmedId":"","doi":"10.1093/genetics/77.1.71"},{"reference":"Cook SJ, Jarrell TA, Brittin CA, Wang Y, Bloniarz AE, Yakovlev MA, et al., Emmons SW. 2019. Whole-animal connectomes of both Caenorhabditis elegans sexes.","pubmedId":"","doi":"10.1038/s41586-019-1352-7"},{"reference":"Goriely A. 2024. Eighty-six billion and counting: do we know the number of neurons in the human brain?.","pubmedId":"","doi":"10.1093/brain/awae390"},{"reference":"Palacios Prado N, Chapuis S, Panjkovich A, Freitas Andrade M, Naus CC, Bukauskas FF. 2014. Molecular determinants of voltage gating in innexin large-pore gap junction channels.","pubmedId":"","doi":"10.1016/j.bpj.2014.02.034"},{"reference":"Phelan P, Goulding DA, Tam JL, Allen MJ, Curtin KD, Bacon JP. 2008. Molecular mechanism of rectification at an electrical synapse.","pubmedId":"","doi":"10.1016/j.cub.2008.02.073"},{"reference":"Shui Y, Liu P, Chen B, Wang ZW. 2020. Molecular basis of junctional current rectification at an electrical synapse.","pubmedId":"","doi":"10.1126/sciadv.abb3076"},{"reference":"Simonsen KT, Moerman DG, Naus CC. 2014. Gap junctions in C. elegans.","pubmedId":"","doi":"10.3389/fphys.2014.00040"},{"reference":"Sohl G, Maxeiner S, Willecke K. 2005. Expression and functions of neuronal gap junctions.","pubmedId":"","doi":"10.1038/nrn1627"},{"reference":"Starich TA, Lee RY, Panzarella C, Avery L, Shaw JE. 1996. eat-5 and unc-7 encode innexin gap junction proteins in Caenorhabditis elegans.","pubmedId":"","doi":"10.1083/jcb.134.2.537"},{"reference":"Starich TA, Xu J, Skerrett IM, Nicholson BJ, Shaw JE. 2009. Interactions between C. elegans innexins UNC-7 and UNC-9 in heterotypic electrical synapses.","pubmedId":"","doi":"10.1091/mbc.e09-03-0251"},{"reference":"Taylor SR, Santpere G, Weinreb A, Barrett A, Sethi AK, Barkoulas M, Miller DM. 2021. Molecular topography of the adult Caenorhabditis elegans nervous system.","pubmedId":"","doi":"10.1016/j.cell.2021.06.023"},{"reference":"Wen Q, Po MD, Hulme E, Patel S, Liu X, Greenwood M, Samuel AD. 2012. Proprioceptive coupling within motor neurons drives C. elegans locomotion.","pubmedId":"","doi":"10.1016/j.neuron.2012.08.039"},{"reference":"White JG, Southgate E, Thomson JN, Brenner S. 1986. The structure of the nervous system of the nematode Caenorhabditis elegans.","pubmedId":"","doi":"10.1098/rstb.1986.0056"}],"title":"Gap junction innexin asymmetry in C. elegans suggests a diode blocking mechanism to prevent antidromic backpropagation from motor neurons to command interneurons","reviews":[],"curatorReviews":[{"curator":{"displayName":"Gary Craig Schindelman"},"openAcknowledgement":false,"submitted":"1787157306993"}]},{"id":"e93e3695-e43c-4e2a-b33f-ed131538f237","decision":"accept","abstract":"In C. elegans, gap junctions between command interneurons and motor neurons mediate rapid behavioural transitions. However, antidromic backpropagation driven by the putative proprioceptive activity of motor neurons with Extended Longitudinal Neurites (ELNs) must be blocked to maintain circuit directionality. Analysing single-cell transcriptomics (CeNGEN), I identify systematic innexin gene expression asymmetry across major motor circuit electrical synapses. Presynaptic interneurons and postsynaptic motor neurons express distinct, non-overlapping innexin subunits. This molecular asymmetry suggests a rectified, diode-like gating mechanism that favours orthodromic signalling while preventing antidromic backpropagation from proprioceptive motor neurons, providing a structural framework for directional electrical transmission.
","acknowledgements":"","authors":[{"affiliations":["University of Wisconsin–Madison, Madison, WI, United States"],"departments":["Emeritus Professor"],"credit":["conceptualization","formalAnalysis","writing_originalDraft"],"email":"kc9fyh@gmail.com","firstName":"John","lastName":"White","submittingAuthor":true,"correspondingAuthor":true,"equalContribution":false,"WBId":null,"orcid":null}],"awards":[],"conflictsOfInterest":"The authors declare that there are no conflicts of interest present.
","dataTable":{"url":null},"extendedData":[],"funding":"No funding used
","image":{"url":"https://portal.micropublication.org/uploads/d16cda41f9b86b7f38e8e4e38fd7c0d5.png"},"imageCaption":"Expression asymmetry of gap junction innexins suggests a rectifying diode isolation mechanism between command interneurons and motor circuit processes.
(A) Innexin expression matrix in identified neurons. Single-cell RNA-seq expression levels (mean TPM, CeNGEN adult dataset; Taylor et al., 2021) of innexins (unc-7, unc-9, inx-21, inx-22, eat-5, and inx-19) in head motor neurons (SMB, SMD), body motor neurons (VA, VB), and associated interneurons (AVA, AVB, RIB, SAA). Bold values highlight dominant expression or key asymmetrical ratios. Note the pronounced unc-7/unc-9 expression ratio skew toward command interneurons (AVA: 6.15; AVB: 5.65; SAA: 3.87). The mean unc-7/unc-9 ratio for all co-expressing neurons in the organism is 1.60. AVB exhibits a high unc-7/unc-9 ratio together with selective expression of the asymmetric innexin inx-19. SAA also exhibits a high unc-7/unc-9 ratio together with selective expression of the asymmetric innexin eat-5. (B) Putative electrical synapses in body motor neuron circuitry. Schematic representation of asymmetric gap junctions between command interneurons (AVA, AVB) and ventral cord motor neurons (VA, VB). Heterotypic coupling between UNC-7 (interneuron side) and UNC-9 (motor neuron side), as well as selective INX-19 expression in AVB, suggests the presence of functional electrical diodes (indicated by diode symbols) configured to pass depolarizing current anterograde while blocking antidromic back-propagation (Starich et al., 2009; Liu et al., 2020). Green bars indicate the presence of distal, uninnervated process extensions hypothesized to function as proprioceptive stretch receptors (White et al., 1986; Wen et al., 2012). AVA also makes chemical synapses onto VA motor neurons (indicated by arrow). (C) Putative electrical synapses in head motor neuron circuitry. Circuit diagram showing asymmetrical gap junctions between head motor neurons (SMB, SMD) and head interneurons (RIB, SAA). EAT-5 is selectively expressed in SMB and SAA, while both INX-21 and INX-22 are selectively expressed in SMD, establishing distinct asymmetric electrical coupling in head motor neuron circuitry (Starich et al., 1996; Simonsen et al., 2014). RIB is a major hub interneuron of the central nervous system (White et al., 1986; Cook et al., 2019). The rectifying electrical connections to SMB and SMD act to isolate RIB from the back-propagation of local electrical activity produced by the proprioceptive activation of SMB and SMD. SAA makes a chemical synapse (arrow) onto SMD in addition to its electrical connection to SMB. (D) Process morphology of body motor neurons VA3 and VB4. Anatomical schematics depicting the extended, morphologically undifferentiated distal processes (green) of VA3 and VB4 extending beyond neuromuscular junction zones (red bars). (E) Process morphology of dorsal head motor neurons SMBDL and SMDDL. Anatomical schematics illustrating the process trajectories of SMBDL and SMDDL, highlighting distal sensory/proprioceptive extensions (green) relative to synaptic output regions within the nerve ring (red). These processes run down the length of the body in small sub-lateral cords. Cell bodies are shown in black. Panels (D) and (E) adapted from White et al. (1986).
","imageTitle":"Innexin asymmetries in motor neuron circuitry
","methods":"Transcriptomic and Connectomic Data Analysis
Single-cell RNA sequencing expression levels (Transcripts Per Million, TPM) for all 25 Caenorhabditis elegans innexins across 133 identified neuronal cell types were extracted from the adult CeNGEN dataset (Taylor et al., 2021). Co-expression frequencies and mean expression ratios were calculated using custom Python scripts running in Google Colab (Python 3.10; pandas v2.0, numpy v1.24). Neuronal co-expression of unc-7 and unc-9 was defined as non-zero TPM values (>0.0 TPM) in both genes across the 133 annotated neuron classes. Anatomical connectivity, chemical and electrical synapse counts, and motor neuron process morphologies were cross-referenced against the EM connectome datasets (White et al., 1986; Cook et al., 2019) and WormAtlas (Altun et al., 2009).
","reagents":"","patternDescription":"The nervous system of C. elegans comprises a total complement of only 302 neurons, yet contains the foundational circuit principles of vertebrate nervous systems, which, in humans, contain about 86 billion neurons (Goriely, 2024). In the mid-1960s, Sydney Brenner pioneered the use of C. elegans as a genetic model system to dissect nervous system development and function (Brenner, 1974). Since then, extensive research has generated comprehensive datasets detailing both the structural connectivity of the nervous system (White et al., 1986; Cook et al., 2019) and single-cell gene expression patterns across development (Taylor et al., 2021). These data are curated in publicly accessible databases such as WormAtlas (Altun et al., 2009) and CeNGEN (Caenorhabditis elegans Neuronal Gene Expression Network) (Taylor et al., 2021).
Gap junctions are specialized ion channels that facilitate electrical coupling between cells (Sohl et al., 2005). They are made up of innexin subunits (connexins in vertebrates), of which there are 25 in C. elegans (Starich et al., 1996; Simonsen et al., 2014). In this study, I analyse the expression of innexins in identified motor neurons and command interneurons. Specifically, I examine the spectrum of expressed innexins at coupled electrical synapses, where striking molecular asymmetries suggest these junctions function as rectifying diodes (Starich et al., 2009; Liu et al., 2020).
The expression maps of the 25 C. elegans innexins reveal two general patterns: generalized expression, such as unc-7 and unc-9 which are co-expressed across 69.9% of all neurons, and restricted expression, where certain innexins exhibit relatively high expression in small neuronal subsets, such as inx-21 and inx-22 which are uniquely expressed in SMD neurons (Taylor et al., 2021).
A generic gap junction is broadly considered a symmetrical structure that permits bidirectional passage of ions or small molecules between coupled cells (Sohl et al., 2005). However, functionally asymmetric electrical synapses have been described that preferentially permit current flow in one direction (Phelan et al., 2008; Starich et al., 2009; Liu et al., 2020). Such gap junctions are structurally asymmetric, most straightforwardly achieved by incorporating differing innexin subunits into the paired hemichannels of adjacent cells (Palacios-Prado et al., 2014).
Figure 1A details examples of molecular asymmetry in neural circuits associated with major motor neurons innervating body wall muscles (VA, VB) and head muscles (SMB, SMD). These classes of neuron all have Extended Longitudinal Neurites (ELNs). One prominent form of asymmetry involves the stoichiometric ratio of the widely expressed innexins unc-7 and unc-9. While the mean organism-wide unc-7/unc-9 ratio across co-expressing neurons is 1.60, major command interneurons AVA and AVB exhibit ratios of 6.15 and 5.65, respectively—nearly four times the neuronal baseline. Even more prominent innexin asymmetries are demonstrated by the restricted expression of inx-21 and inx-22 in SMD and eat-5 in SMB and SAA.
Strikingly, these asymmetrical gap junctions selectively involve circuitry tied to motor neurons driving body (VA, VB) and head (SMB, SMD) locomotion (Fig. 1B, C). All these motor neuron classes share the hallmark anatomical feature of ELNs: morphologically undifferentiated longitudinal processes situated distal to their neuromuscular output zones (Fig. 1D, E). It has long been posited that these distal extensions act as proprioceptors, transducing local body bending into downstream muscle activation during undulatory locomotion (White et al., 1986; Wen et al., 2012).
Rectifying gap junctions function effectively as blocking diodes that restrict ionic current flow to a single direction (Shui et al., 2020). For motor neurons possessing dual motor-proprioceptive modalities (VA, VB, SMB, SMD), diode rectification would be vital to prevent locally generated, stretch-activated electrical signals from back-propagating antidromically into critical central interneurons, such as the major network hub RIB (Fig. 1C). Supporting this hypothesis, major motor neurons lacking extended proprioceptive process extensions, such as RMD, exhibit no corresponding innexin asymmetries in their gap junctions.
Combining connectomic mapping with cell-specific transcriptomic profiling can provide key functional insights into neural circuitry. Such findings provide testable hypotheses to guide future electrophysiological experiments and computational modelling aimed at deciphering how a nervous system generates the behaviours that control an organism.
","references":[{"reference":"Altun ZF, Herndon LA, Wolkow CA, Crocker C, Lints R, Hall DH. 2009. WormAtlas. https://www.wormatlas.org/
","pubmedId":"","doi":""},{"reference":"Brenner S. 1974. The genetics of Caenorhabditis elegans.","pubmedId":"","doi":"10.1093/genetics/77.1.71"},{"reference":"Cook SJ, Jarrell TA, Brittin CA, Wang Y, Bloniarz AE, Yakovlev MA, et al., Emmons SW. 2019. Whole-animal connectomes of both Caenorhabditis elegans sexes.","pubmedId":"","doi":"10.1038/s41586-019-1352-7"},{"reference":"Goriely A. 2024. Eighty-six billion and counting: do we know the number of neurons in the human brain?.","pubmedId":"","doi":"10.1093/brain/awae390"},{"reference":"Palacios Prado N, Chapuis S, Panjkovich A, Freitas Andrade M, Naus CC, Bukauskas FF. 2014. Molecular determinants of voltage gating in innexin large-pore gap junction channels.","pubmedId":"","doi":"10.1016/j.bpj.2014.02.034"},{"reference":"Phelan P, Goulding DA, Tam JL, Allen MJ, Curtin KD, Bacon JP. 2008. Molecular mechanism of rectification at an electrical synapse.","pubmedId":"","doi":"10.1016/j.cub.2008.02.073"},{"reference":"Shui Y, Liu P, Chen B, Wang ZW. 2020. Molecular basis of junctional current rectification at an electrical synapse.","pubmedId":"","doi":"10.1126/sciadv.abb3076"},{"reference":"Simonsen KT, Moerman DG, Naus CC. 2014. Gap junctions in C. elegans.","pubmedId":"","doi":"10.3389/fphys.2014.00040"},{"reference":"Sohl G, Maxeiner S, Willecke K. 2005. Expression and functions of neuronal gap junctions.","pubmedId":"","doi":"10.1038/nrn1627"},{"reference":"Starich TA, Lee RY, Panzarella C, Avery L, Shaw JE. 1996. eat-5 and unc-7 encode innexin gap junction proteins in Caenorhabditis elegans.","pubmedId":"","doi":"10.1083/jcb.134.2.537"},{"reference":"Starich TA, Xu J, Skerrett IM, Nicholson BJ, Shaw JE. 2009. Interactions between C. elegans innexins UNC-7 and UNC-9 in heterotypic electrical synapses.","pubmedId":"","doi":"10.1091/mbc.e09-03-0251"},{"reference":"Taylor SR, Santpere G, Weinreb A, Barrett A, Sethi AK, Barkoulas M, Miller DM. 2021. Molecular topography of the adult Caenorhabditis elegans nervous system.","pubmedId":"","doi":"10.1016/j.cell.2021.06.023"},{"reference":"Wen Q, Po MD, Hulme E, Patel S, Liu X, Greenwood M, Samuel AD. 2012. Proprioceptive coupling within motor neurons drives C. elegans locomotion.","pubmedId":"","doi":"10.1016/j.neuron.2012.08.039"},{"reference":"White JG, Southgate E, Thomson JN, Brenner S. 1986. The structure of the nervous system of the nematode Caenorhabditis elegans.","pubmedId":"","doi":"10.1098/rstb.1986.0056"}],"title":"Gap junction innexin asymmetry in C. elegans suggests a diode blocking mechanism to prevent antidromic backpropagation from motor neurons to command interneurons","reviews":[],"curatorReviews":[{"curator":{"displayName":"Gary Craig Schindelman"},"openAcknowledgement":false,"submitted":null}]},{"id":"98b230ff-ba7b-4dd7-b04d-62d6cb64e24c","decision":"publish","abstract":"In C. elegans, gap junctions between command interneurons and motor neurons mediate rapid behavioural transitions. However, antidromic backpropagation driven by the putative proprioceptive activity of motor neurons with Extended Longitudinal Neurites (ELNs) must be blocked to maintain circuit directionality. Analysing single-cell transcriptomics (CeNGEN), I identify systematic innexin gene expression asymmetry across major motor circuit electrical synapses. Presynaptic interneurons and postsynaptic motor neurons express distinct, non-overlapping innexin subunits. This molecular asymmetry suggests a rectified, diode-like gating mechanism that favours orthodromic signalling while preventing antidromic backpropagation from proprioceptive motor neurons, providing a structural framework for directional electrical transmission.
","acknowledgements":"","authors":[{"affiliations":["University of Wisconsin–Madison, Madison, WI, United States"],"departments":["Emeritus Professor"],"credit":["conceptualization","formalAnalysis","writing_originalDraft"],"email":"kc9fyh@gmail.com","firstName":"John","lastName":"White","submittingAuthor":true,"correspondingAuthor":true,"equalContribution":false,"WBId":null,"orcid":null}],"awards":[],"conflictsOfInterest":"The authors declare that there are no conflicts of interest present.
","dataTable":{"url":null},"extendedData":[],"funding":"No funding used
","image":{"url":"https://portal.micropublication.org/uploads/d16cda41f9b86b7f38e8e4e38fd7c0d5.png"},"imageCaption":"Expression asymmetry of gap junction innexins suggests a rectifying diode isolation mechanism between command interneurons and motor circuit processes.
(A) Innexin expression matrix in identified neurons. Single-cell RNA-seq expression levels (mean TPM, CeNGEN adult dataset; Taylor et al., 2021) of innexins (unc-7, unc-9, inx-21, inx-22, eat-5, and inx-19) in head motor neurons (SMB, SMD), body motor neurons (VA, VB), and associated interneurons (AVA, AVB, RIB, SAA). Gray boxes highlight dominant expression or key asymmetrical ratios. Note the pronounced unc-7/unc-9 expression ratio skew toward command interneurons (AVA: 6.15; AVB: 5.65; SAA: 3.87). The mean unc-7/unc-9 ratio for all co-expressing neurons in the organism is 1.60. AVB exhibits a high unc-7/unc-9 ratio together with selective expression of the asymmetric innexin inx-19. SAA also exhibits a high unc-7/unc-9 ratio together with selective expression of the asymmetric innexin eat-5. (B) Putative electrical synapses in body motor neuron circuitry. Schematic representation of asymmetric gap junctions between command interneurons (AVA, AVB) and ventral cord motor neurons (VA, VB). Heterotypic coupling between UNC-7 (interneuron side) and UNC-9 (motor neuron side), as well as selective INX-19 expression in AVB, suggests the presence of functional electrical diodes (indicated by diode symbols) configured to pass depolarizing current anterograde while blocking antidromic back-propagation (Starich et al., 2009; Liu et al., 2020). Green bars indicate the presence of distal, uninnervated process extensions hypothesized to function as proprioceptive stretch receptors (White et al., 1986; Wen et al., 2012). AVA also makes chemical synapses onto VA motor neurons (indicated by arrow). (C) Putative electrical synapses in head motor neuron circuitry. Circuit diagram showing asymmetrical gap junctions between head motor neurons (SMB, SMD) and head interneurons (RIB, SAA). EAT-5 is selectively expressed in SMB and SAA, while both INX-21 and INX-22 are selectively expressed in SMD, establishing distinct asymmetric electrical coupling in head motor neuron circuitry (Starich et al., 1996; Simonsen et al., 2014). RIB is a major hub interneuron of the central nervous system (White et al., 1986; Cook et al., 2019). The rectifying electrical connections to SMB and SMD act to isolate RIB from the back-propagation of local electrical activity produced by the proprioceptive activation of SMB and SMD. SAA makes a chemical synapse (arrow) onto SMD in addition to its electrical connection to SMB. (D) Process morphology of body motor neurons VA3 and VB4. Anatomical schematics depicting the extended, morphologically undifferentiated distal processes (green) of VA3 and VB4 extending beyond neuromuscular junction zones (red bars). (E) Process morphology of dorsal head motor neurons SMBDL and SMDDL. Anatomical schematics illustrating the process trajectories of SMBDL and SMDDL, highlighting distal sensory/proprioceptive extensions (green) relative to synaptic output regions within the nerve ring (red). These processes run down the length of the body in small sub-lateral cords. Cell bodies are shown in black. Panels (D) and (E) adapted from White et al. (1986).
","imageTitle":"Innexin asymmetries in motor neuron circuitry
","methods":"Transcriptomic and Connectomic Data Analysis
Single-cell RNA sequencing expression levels (Transcripts Per Million, TPM) for all 25 Caenorhabditis elegans innexins across 133 identified neuronal cell types were extracted from the adult CeNGEN dataset (Taylor et al., 2021). Co-expression frequencies and mean expression ratios were calculated using custom Python scripts running in Google Colab (Python 3.10; pandas v2.0, numpy v1.24). Neuronal co-expression of unc-7 and unc-9 was defined as non-zero TPM values (>0.0 TPM) in both genes across the 133 annotated neuron classes. Anatomical connectivity, chemical and electrical synapse counts, and motor neuron process morphologies were cross-referenced against the EM connectome datasets (White et al., 1986; Cook et al., 2019) and WormAtlas (Altun et al., 2009).
","reagents":"","patternDescription":"The nervous system of C. elegans comprises a total complement of only 302 neurons, yet contains the foundational circuit principles of vertebrate nervous systems, which, in humans, contain about 86 billion neurons (Goriely, 2024). In the mid-1960s, Sydney Brenner pioneered the use of C. elegans as a genetic model system to dissect nervous system development and function (Brenner, 1974). Since then, extensive research has generated comprehensive datasets detailing both the structural connectivity of the nervous system (White et al., 1986; Cook et al., 2019) and single-cell gene expression patterns across development (Taylor et al., 2021). These data are curated in publicly accessible databases such as WormAtlas (Altun et al., 2009) and CeNGEN (Caenorhabditis elegans Neuronal Gene Expression Network) (Taylor et al., 2021).
Gap junctions are specialized ion channels that facilitate electrical coupling between cells (Sohl et al., 2005). They are made up of innexin subunits (connexins in vertebrates), of which there are 25 in C. elegans (Starich et al., 1996; Simonsen et al., 2014). In this study, I analyse the expression of innexins in identified motor neurons and command interneurons. Specifically, I examine the spectrum of expressed innexins at coupled electrical synapses, where striking molecular asymmetries suggest these junctions function as rectifying diodes (Starich et al., 2009; Liu et al., 2020).
The expression maps of the 25 C. elegans innexins reveal two general patterns: generalized expression, such as unc-7 and unc-9 which are co-expressed across 69.9% of all neurons, and restricted expression, where certain innexins exhibit relatively high expression in small neuronal subsets, such as inx-21 and inx-22 which are uniquely expressed in SMD neurons (Taylor et al., 2021).
A generic gap junction is broadly considered a symmetrical structure that permits bidirectional passage of ions or small molecules between coupled cells (Sohl et al., 2005). However, functionally asymmetric electrical synapses have been described that preferentially permit current flow in one direction (Phelan et al., 2008; Starich et al., 2009; Liu et al., 2020). Such gap junctions are structurally asymmetric, most straightforwardly achieved by incorporating differing innexin subunits into the paired hemichannels of adjacent cells (Palacios-Prado et al., 2014).
Figure 1A details examples of molecular asymmetry in neural circuits associated with major motor neurons innervating body wall muscles (VA, VB) and head muscles (SMB, SMD). These classes of neuron all have Extended Longitudinal Neurites (ELNs). One prominent form of asymmetry involves the stoichiometric ratio of the widely expressed innexins unc-7 and unc-9. While the mean organism-wide unc-7/unc-9 ratio across co-expressing neurons is 1.60, major command interneurons AVA and AVB exhibit ratios of 6.15 and 5.65, respectively—nearly four times the neuronal baseline. Even more prominent innexin asymmetries are demonstrated by the restricted expression of inx-21 and inx-22 in SMD and eat-5 in SMB and SAA.
Strikingly, these asymmetrical gap junctions selectively involve circuitry tied to motor neurons driving body (VA, VB) and head (SMB, SMD) locomotion (Fig. 1B, C). All these motor neuron classes share the hallmark anatomical feature of ELNs: morphologically undifferentiated longitudinal processes situated distal to their neuromuscular output zones (Fig. 1D, E). It has long been posited that these distal extensions act as proprioceptors, transducing local body bending into downstream muscle activation during undulatory locomotion (White et al., 1986; Wen et al., 2012).
Rectifying gap junctions function effectively as blocking diodes that restrict ionic current flow to a single direction (Shui et al., 2020). For motor neurons possessing dual motor-proprioceptive modalities (VA, VB, SMB, SMD), diode rectification would be vital to prevent locally generated, stretch-activated electrical signals from back-propagating antidromically into critical central interneurons, such as the major network hub RIB (Fig. 1C). Supporting this hypothesis, major motor neurons lacking extended proprioceptive process extensions, such as RMD, exhibit no corresponding innexin asymmetries in their gap junctions.
Combining connectomic mapping with cell-specific transcriptomic profiling can provide key functional insights into neural circuitry. Such findings provide testable hypotheses to guide future electrophysiological experiments and computational modelling aimed at deciphering how a nervous system generates the behaviours that control an organism.
","references":[{"reference":"Altun ZF, Herndon LA, Wolkow CA, Crocker C, Lints R, Hall DH. 2009. WormAtlas. https://www.wormatlas.org/
","pubmedId":"","doi":""},{"reference":"Brenner S. 1974. The genetics of Caenorhabditis elegans.","pubmedId":"","doi":"10.1093/genetics/77.1.71"},{"reference":"Cook SJ, Jarrell TA, Brittin CA, Wang Y, Bloniarz AE, Yakovlev MA, et al., Emmons SW. 2019. Whole-animal connectomes of both Caenorhabditis elegans sexes.","pubmedId":"","doi":"10.1038/s41586-019-1352-7"},{"reference":"Goriely A. 2024. Eighty-six billion and counting: do we know the number of neurons in the human brain?.","pubmedId":"","doi":"10.1093/brain/awae390"},{"reference":"Palacios Prado N, Chapuis S, Panjkovich A, Freitas Andrade M, Naus CC, Bukauskas FF. 2014. Molecular determinants of voltage gating in innexin large-pore gap junction channels.","pubmedId":"","doi":"10.1016/j.bpj.2014.02.034"},{"reference":"Phelan P, Goulding DA, Tam JL, Allen MJ, Curtin KD, Bacon JP. 2008. Molecular mechanism of rectification at an electrical synapse.","pubmedId":"","doi":"10.1016/j.cub.2008.02.073"},{"reference":"Shui Y, Liu P, Chen B, Wang ZW. 2020. Molecular basis of junctional current rectification at an electrical synapse.","pubmedId":"","doi":"10.1126/sciadv.abb3076"},{"reference":"Simonsen KT, Moerman DG, Naus CC. 2014. Gap junctions in C. elegans.","pubmedId":"","doi":"10.3389/fphys.2014.00040"},{"reference":"Sohl G, Maxeiner S, Willecke K. 2005. Expression and functions of neuronal gap junctions.","pubmedId":"","doi":"10.1038/nrn1627"},{"reference":"Starich TA, Lee RY, Panzarella C, Avery L, Shaw JE. 1996. eat-5 and unc-7 encode innexin gap junction proteins in Caenorhabditis elegans.","pubmedId":"","doi":"10.1083/jcb.134.2.537"},{"reference":"Starich TA, Xu J, Skerrett IM, Nicholson BJ, Shaw JE. 2009. Interactions between C. elegans innexins UNC-7 and UNC-9 in heterotypic electrical synapses.","pubmedId":"","doi":"10.1091/mbc.e09-03-0251"},{"reference":"Taylor SR, Santpere G, Weinreb A, Barrett A, Sethi AK, Barkoulas M, Miller DM. 2021. Molecular topography of the adult Caenorhabditis elegans nervous system.","pubmedId":"","doi":"10.1016/j.cell.2021.06.023"},{"reference":"Wen Q, Po MD, Hulme E, Patel S, Liu X, Greenwood M, Samuel AD. 2012. Proprioceptive coupling within motor neurons drives C. elegans locomotion.","pubmedId":"","doi":"10.1016/j.neuron.2012.08.039"},{"reference":"White JG, Southgate E, Thomson JN, Brenner S. 1986. The structure of the nervous system of the nematode Caenorhabditis elegans.","pubmedId":"","doi":"10.1098/rstb.1986.0056"}],"title":"Gap junction innexin asymmetry in C. elegans suggests a diode blocking mechanism to prevent antidromic backpropagation from motor neurons to command interneurons","reviews":[],"curatorReviews":[{"curator":{"displayName":"Gary Craig Schindelman"},"openAcknowledgement":false,"submitted":null}]}]}},"species":{"species":[{"value":"acer saccharum","label":"Acer saccharum","imageSrc":"","imageAlt":"","mod":"TreeGenes","modLink":"https://treegenesdb.org","linkVariable":""},{"value":"achillea millefolium","label":"Achillea millefolium","imageSrc":"","imageAlt":"","mod":"","modLink":"","linkVariable":""},{"value":"acinetobacter baylyi","label":"Acinetobacter baylyi","imageSrc":"","imageAlt":"","mod":"","modLink":"","linkVariable":""},{"value":"actinobacteria bacterium","label":"Actinobacteria 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