Uncovering the genetic blueprint of the C. elegans nervous system

Despite rapid advances in connectome mapping and neuronal genetics, we lack theoretical and computational tools to unveil, in an experimentally testable fashion, the genetic mechanisms that govern neuronal wiring. Here we introduce a computational framework to link the adjacency matrix of a connectome to the expression patterns of its neurons, helping us uncover a set of genetic rules that govern the interactions between adjacent neurons. The method incorporates the biological realities of the system, accounting for noise from data collection limitations, as well as spatial restrictions. The resulting methodology allows us to infer a network of 19 innexin interactions that govern the formation of gap junctions in C. elegans, five of which are already supported by experimental data. As advances in single-cell gene expression profiling increase the accuracy and the coverage of the data, the developed framework will allow researchers to systematically infer experimentally testable connection rules, offering mechanistic predictions for synapse and gap junction formation.

[1]  Kimberly Van Auken,et al.  WormBase: a comprehensive resource for nematode research , 2009, Nucleic Acids Res..

[2]  Thomas L. Dean,et al.  The atoms of neural computation , 2014, Science.

[3]  G. Buzsáki,et al.  Pyramidal Cell-Interneuron Circuit Architecture and Dynamics in Hippocampal Networks , 2017, Neuron.

[4]  Isaac Meilijson,et al.  Gene Expression of Caenorhabditis elegans Neurons Carries Information on Their Synaptic Connectivity , 2006, PLoS Comput. Biol..

[5]  Cori Bargmann,et al.  An Innexin-Dependent Cell Network Establishes Left-Right Neuronal Asymmetry in C. elegans , 2007, Cell.

[6]  Frederico A. C. Azevedo,et al.  Equal numbers of neuronal and nonneuronal cells make the human brain an isometrically scaled‐up primate brain , 2009, The Journal of comparative neurology.

[7]  Oscar Marín,et al.  Development and Functional Diversification of Cortical Interneurons , 2018, Neuron.

[8]  Zeynep F. Altun,et al.  Six Innexins Contribute to Electrical Coupling of C. elegans Body-Wall Muscle , 2013, PloS one.

[9]  D. Hall.  Gap junctions in C. elegans: Their roles in behavior and development , 2016, Developmental neurobiology.

[10]  A. Barabasi,et al.  Fractal Concepts in Surface Growth: Frontmatter , 1995 .

[11]  Justus M. Kebschull,et al.  The logic of single-cell projections from visual cortex , 2018, Nature.

[12]  W. Wadsworth,et al.  Identification of Domains of Netrin UNC-6 that Mediate Attractive and Repulsive Guidance and Responses from Cells and Growth Cones , 2002, The Journal of Neuroscience.

[13]  G. Fishell,et al.  Interneuron Types as Attractors and Controllers. , 2020, Annual review of neuroscience.

[14]  A. Barabasi,et al.  Fractal concepts in surface growth , 1995 .

[15]  Z. J. Huang,et al.  Transcriptional Architecture of Synaptic Communication Delineates GABAergic Neuron Identity , 2017, Cell.

[16]  Yi Wang,et al.  Whole-animal connectomes of both Caenorhabditis elegans sexes , 2019, Nature.

[17]  Richard Roy,et al.  Regulation of intermuscular electrical coupling by the Caenorhabditis elegans innexin inx-6. , 2003, Molecular biology of the cell.

[18]  Oliver Hobert,et al.  Revisiting Neuronal Cell Type Classification in Caenorhabditis elegans , 2016, Current Biology.

[19]  Sean M. O'Rourke,et al.  A Survey of New Temperature-Sensitive, Embryonic-Lethal Mutations in C. elegans: 24 Alleles of Thirteen Genes , 2011, PloS one.

[20]  David M. Miller,et al.  Computational inference of the molecular logic for synaptic connectivity in C. elegans , 2006, ISMB.

[21]  Eran Segal,et al.  Using Expression Profiles of Caenorhabditis elegans Neurons To Identify Genes That Mediate Synaptic Connectivity , 2008, PLoS Comput. Biol..

[22]  Alison T. DePew,et al.  The Tenets of Teneurin: Conserved Mechanisms Regulate Diverse Developmental Processes in the Drosophila Nervous System , 2018, bioRxiv.

[23]  Lav R. Varshney,et al.  Structural Properties of the Caenorhabditis elegans Neuronal Network , 2009, PLoS Comput. Biol..

[24]  Allan Sly,et al.  Random graphs with a given degree sequence , 2010, 1005.1136.

[25]  Zeynep F. Altun,et al.  High resolution map of Caenorhabditis elegans gap junction proteins , 2009, Developmental dynamics : an official publication of the American Association of Anatomists.

[26]  G. G. Stokes.  "J." , 1890, The New Yale Book of Quotations.

[27]  Henry Kennedy,et al.  A Predictive Network Model of Cerebral Cortical Connectivity Based on a Distance Rule , 2013, Neuron.

[28]  H. Seung,et al.  Neuronal Cell Types and Connectivity: Lessons from the Retina , 2014, Neuron.

[29]  D. Hall,et al.  The unc-5, unc-6, and unc-40 genes guide circumferential migrations of pioneer axons and mesodermal cells on the epidermis in C. elegans , 1990, Neuron.

[30]  Cornelia I Bargmann,et al.  Synaptic Specificity Is Generated by the Synaptic Guidepost Protein SYG-2 and Its Receptor, SYG-1 , 2004, Cell.

[31]  J. Bacon,et al.  Two Drosophila innexins are expressed in overlapping domains and cooperate to form gap-junction channels. , 2000, Molecular biology of the cell.

[32]  István A. Kovács,et al.  Widespread Macromolecular Interaction Perturbations in Human Genetic Disorders , 2015, Cell.

[33]  L. Luo,et al.  Genetic Control of Wiring Specificity in the Fly Olfactory System , 2014, Genetics.

[34]  K. Sneppen,et al.  Specificity and Stability in Topology of Protein Networks , 2002, Science.

[35]  William R Schafer,et al.  Engineering new synaptic connections in the C. elegans connectome , 2015, Worm.

[36]  Cori Bargmann,et al.  Shared receptors in axon guidance: SAX-3/Robo signals via UNC-34/Enabled and a Netrin-independent UNC-40/DCC function , 2002, Nature Neuroscience.

[37]  W. Rappel,et al.  Self-organization in systems of self-propelled particles. , 2000, Physical review. E, Statistical, nonlinear, and soft matter physics.

[38]  Goldenfeld,et al.  Simple lessons from complexity , 1999, Science.

[39]  W. Cowan,et al.  Annual Review of Neuroscience , 1995 .

[40]  Christof Koch,et al.  Adult Mouse Cortical Cell Taxonomy by Single Cell Transcriptomics , 2016, Nature Neuroscience.

[41]  Cornelia I Bargmann,et al.  UNC-6/Netrin induces neuronal asymmetry and defines the site of axon formation , 2006, Nature Neuroscience.

[42]  Albert-László Barabási,et al.  A Genetic Model of the Connectome , 2019, Neuron.

[43]  Nigel Goldenfeld,et al.  Scale-invariant topology and bursty branching of evolutionary trees emerge from niche construction , 2020, Proceedings of the National Academy of Sciences.

[44]  T. Südhof,et al.  Synaptic Neurexin Complexes: A Molecular Code for the Logic of Neural Circuits , 2017, Cell.

[45]  Travis A. Jarrell,et al.  The Connectome of a Decision-Making Neural Network , 2012, Science.

[46]  S. Linnarsson,et al.  Cell types in the mouse cortex and hippocampus revealed by single-cell RNA-seq , 2015, Science.

[47]  O. Hobert,et al.  Plasticity of the Electrical Connectome of C. elegans , 2019, Cell.

[48]  Hugo J. Bellen,et al.  Control of Synaptic Connectivity by a Network of Drosophila IgSF Cell Surface Proteins , 2015, Cell.

[49]  K. Willecke,et al.  Expression and functions of neuronal gap junctions , 2005, Nature Reviews Neuroscience.

[50]  Yoshinori Fujiyoshi,et al.  Oligomeric Structure and Functional Characterization of Caenorhabditis elegans Innexin-6 Gap Junction Protein* , 2013, The Journal of Biological Chemistry.

[51]  Alexander Meissner,et al.  Highly efficient reprogramming to pluripotency and directed differentiation of human cells with synthetic modified mRNA. , 2010, Cell stem cell.

[52]  S. Brenner,et al.  The structure of the nervous system of the nematode Caenorhabditis elegans. , 1986, Philosophical transactions of the Royal Society of London. Series B, Biological sciences.