Neurogenesis in the nematode Caenorhabditis elegans.

The nervous system represents the most complex tissue of C. elegans both in terms of numbers (302 neurons and 56 glial cells = 37% of the somatic cells in a hermaphrodite) and diversity (118 morphologically distinct neuron classes). The lineage and morphology of each neuron type has been described in detail and neuronal fate markers exists for virtually all neurons in the form of fluorescent reporter genes. The ability to "phenotype" neurons at high resolution combined with the amenability of C. elegans to genetic mutant analysis make the C. elegans nervous system a prime model system to elucidate the nature of the gene regulatory programs that build a nervous system-a central question of developmental neurobiology. Discussing a number of regulatory genes involved in neuronal lineage determination and neuronal differentiation, I will try to carve out in this review a few general principles of neuronal development in C. elegans. These principles may be conserved across phylogeny.

[1]  W. W. Walthall,et al.  UNC-55, an Orphan Nuclear Hormone Receptor, Orchestrates Synaptic Specificity among Two Classes of Motor Neurons in Caenorhabditis elegans , 1998, The Journal of Neuroscience.

[2]  J. Sulston,et al.  Post-embryonic cell lineages of the nematode, Caenorhabditis elegans. , 1977, Developmental biology.

[3]  G. Ruvkun,et al.  Control of Neural Development and Function in a Thermoregulatory Network by the Lim Homeobox Gene Lin-11 , 2022 .

[4]  Yishi Jin,et al.  The AHR-1 aryl hydrocarbon receptor and its co-factor the AHA-1 aryl hydrocarbon receptor nuclear translocator specify GABAergic neuron cell fate in C. elegans , 2004, Development.

[5]  C. A. Frank,et al.  The C. elegans MELK ortholog PIG-1 regulates cell size asymmetry and daughter cell fate in asymmetric neuroblast divisions , 2006, Development.

[6]  S. W. Emmons,et al.  Axial patterning of C. elegans male sensilla identities by selector genes. , 2004, Developmental biology.

[7]  Correct Hox gene expression established independently of position in Caenorhabditis elegans , 1996, Nature.

[8]  Sumeet Sarin,et al.  The C. elegans Tailless/TLX transcription factor nhr-67 controls neuronal identity and left/right asymmetric fate diversification , 2009, Development.

[9]  Harald Hutter,et al.  AST-1, a novel ETS-box transcription factor, controls axon guidance and pharynx development in C. elegans. , 2006, Developmental biology.

[10]  O. Hobert,et al.  Architecture of a microRNA-controlled gene regulatory network that diversifies neuronal cell fates. , 2006, Cold Spring Harbor symposia on quantitative biology.

[11]  O. Hobert,et al.  Left–right asymmetry in the nervous system: the Caenorhabditis elegans model , 2002, Nature Reviews Neuroscience.

[12]  M. Chalfie,et al.  Green fluorescent protein as a marker for gene expression. , 1994, Science.

[13]  H. Hutter,et al.  zag-1, a Zn-finger homeodomain transcription factor controlling neuronal differentiation and axon outgrowth in C. elegans , 2003, Development.

[14]  HighWire Press.  Philosophical Transactions of the Royal Society of London , 1781, The London Medical Journal.

[15]  Stephen E Von Stetina,et al.  The motor circuit. , 2006, International review of neurobiology.

[16]  Stephen E. Von Stetina,et al.  UNC-4 represses CEH-12/HB9 to specify synaptic inputs to VA motor neurons in C. elegans. , 2007, Genes & development.

[17]  R. L. Russell,et al.  Chemotaxis-defective mutants of the nematode Caenorhabditis elegans. , 1975, Genetics.

[18]  O. Hobert,et al.  Functional mapping of neurons that control locomotory behavior in Caenorhabditis elegans. , 2003, Journal of neurobiology.

[19]  I. Greenwald,et al.  A Caenorhabditis elegans model for epithelial–neuronal transdifferentiation , 2008, Proceedings of the National Academy of Sciences.

[20]  Oliver Hobert,et al.  A transcriptional regulatory cascade that controls left/right asymmetry in chemosensory neurons of C. elegans. , 2003, Genes & development.

[21]  H. Horvitz,et al.  C. elegans HAM-1 positions the cleavage plane and regulates apoptosis in asymmetric neuroblast divisions. , 2005, Developmental biology.

[22]  Caenorhabditis Elegans Martinchalfieandjohnsulston.  Developmental Genetics of the Mechanosensory Neurons of Caenorhabditis elegans , 2003 .

[23]  Oliver Hobert,et al.  Automated screening for mutants affecting dopaminergic neuron specification in C. elegans , 2008, Nature Methods.

[24]  O. Hobert.  Behavioral plasticity in C. elegans: paradigms, circuits, genes. , 2003, Journal of neurobiology.

[25]  D. Melton,et al.  Vertebrate neural induction. , 1997, Annual review of neuroscience.

[26]  Yishi Jin,et al.  Control of type-D GABAergic neuron differentiation by C. elegans UNC-30 homeodomain protein , 1994, Nature.

[27]  O. Hobert,et al.  The molecular and gene regulatory signature of a neuron , 2010, Trends in Neurosciences.

[28]  Cori Bargmann,et al.  Lateral Signaling Mediated by Axon Contact and Calcium Entry Regulates Asymmetric Odorant Receptor Expression in C. elegans , 1999, Cell.

[29]  R. Waterston,et al.  mls-2 and vab-3 control glia development, hlh-17/Olig expression and glia-dependent neurite extension in C. elegans , 2008, Development.

[30]  Barrett C. Foat,et al.  Identification of genes expressed in C. elegans touch receptor neurons , 2002, Nature.

[31]  B. Durand,et al.  Identification of novel regulatory factor X (RFX) target genes by comparative genomics in Drosophila species , 2007, Genome Biology.

[32]  J E Sulston,et al.  Neuronal cell lineages in the nematode Caenorhabditis elegans. , 1983, Cold Spring Harbor symposia on quantitative biology.

[33]  N. Pujol,et al.  The homeodomain protein CePHOX2/CEH-17 controls antero-posterior axonal growth in C. elegans. , 2000, Development.

[34]  H. Lipkin.  Where is the ?c? , 1978 .

[35]  Y. Jan,et al.  Different Levels of the Homeodomain Protein Cut Regulate Distinct Dendrite Branching Patterns of Drosophila Multidendritic Neurons , 2003, Cell.

[36]  Abstract , 1952 .

[37]  P. Sengupta,et al.  Regulation of chemosensory and GABAergic motor neuron development by the C. elegans Aristaless/Arx homolog alr-1 , 2005, Development.

[38]  L. Avery,et al.  LIM homeobox gene-dependent expression of biogenic amine receptors in restricted regions of the C. elegans nervous system. , 2003, Developmental biology.

[39]  H. Horvitz,et al.  Mutations that affect neural cell lineages and cell fates during the development of the nematode Caenorhabditis elegans. , 1983, Cold Spring Harbor symposia on quantitative biology.

[40]  M. de Bono,et al.  Neuronal substrates of complex behaviors in C. elegans. , 2005, Annual review of neuroscience.

[41]  G. Ruvkun,et al.  Regulation of Interneuron Function in the C. elegans Thermoregulatory Pathway by the ttx-3 LIM Homeobox Gene , 1997, Neuron.

[42]  F. Guillemot.  Spatial and temporal specification of neural fates by transcription factor codes , 2007, Development.

[43]  Cori Bargmann,et al.  C. elegans odour discrimination requires asymmetric diversity in olfactory neurons , 2001, Nature.

[44]  Oliver Hobert,et al.  Early Embryonic Programming of Neuronal Left/Right Asymmetry in C. elegans , 2006, Current Biology.

[45]  J. Hillman,et al.  Identification of genes expressed in cultures of E. coli lysogens carrying the Shiga toxin-encoding prophage Φ24B , 2012, BMC Microbiology.

[46]  I. Greenwald.  Cell-cell interactions that specify certain cell fates in C. elegans development. , 1989, Trends in genetics : TIG.

[47]  O. Hobert,et al.  An Interneuronal Chemoreceptor Required for Olfactory Imprinting in C. elegans , 2005, Science.

[48]  Nektarios Tavernarakis,et al.  UNC-4/UNC-37-dependent repression of motor neuron-specific genes controls synaptic choice in Caenorhabditis elegans. , 1999, Genes & development.

[49]  O. Hobert,et al.  Genomic cis-regulatory architecture and trans-acting regulators of a single interneuron-specific gene battery in C. elegans. , 2004, Developmental cell.

[50]  Stephen E. Von Stetina,et al.  A gene expression fingerprint of C. elegans embryonic motor neurons , 2005, BMC Genomics.

[51]  P. Sengupta,et al.  The HMX/NKX homeodomain protein MLS-2 specifies the identity of the AWC sensory neuron type via regulation of the ceh-36 Otx gene in C. elegans , 2010, Development.

[52]  C. Guenther,et al.  Asymmetric distribution of the C. elegans HAM-1 protein in neuroblasts enables daughter cells to adopt distinct fates. , 1996, Development.

[53]  O. Hobert,et al.  A regulatory cascade of three homeobox genes, ceh-10, ttx-3 and ceh-23, controls cell fate specification of a defined interneuron class in C. elegans. , 2001, Development.

[54]  O. Hobert.  From the Cover: Gene Networks in Development and Evolution Special Feature Sackler Colloquium: Regulatory logic of neuronal diversity: Terminal selector genes and selector motifs , 2008 .

[55]  Scott W. Emmons,et al.  A transcription factor controlling development of peripheral sense organs in C. elegans , 1995, Nature.

[56]  R. Schnabel,et al.  glp-1 and inductions establishing embryonic axes in C. elegans. , 1994, Development.

[57]  S. Keleş,et al.  Expression Profiling of GABAergic Motor Neurons in Caenorhabditis elegans , 2005, Current Biology.

[58]  M. Chalfie,et al.  mec-3, a homeobox-containing gene that specifies differentiation of the touch receptor neurons in C. elegans , 1988, Cell.

[59]  H. Horvitz,et al.  The Caenorhabditis elegans gene lin-26 is required to specify the fates of hypodermal cells and encodes a presumptive zinc-finger transcription factor. , 1994, Development.

[60]  D M Miller,et al.  Expression of the unc-4 homeoprotein in Caenorhabditis elegans motor neurons specifies presynaptic input. , 1995, Development.

[61]  S. Shaham.  Glia–neuron interactions in the nervous system of Caenorhabditis elegans , 2006, Current Opinion in Neurobiology.

[62]  C. A. Frank,et al.  HLH-14 is a C. elegans Achaete-Scute protein that promotes neurogenesis through asymmetric cell division , 2003, Development.

[63]  B. Ye,et al.  unc-3, a gene required for axonal guidance in Caenorhabditis elegans, encodes a member of the O/E family of transcription factors. , 1998, Development.

[64]  Cori Bargmann,et al.  Otx/otd homeobox genes specify distinct sensory neuron identities in C. elegans. , 2003, Developmental cell.

[65]  Cori Bargmann,et al.  The CaMKII UNC-43 Activates the MAPKKK NSY-1 to Execute a Lateral Signaling Decision Required for Asymmetric Olfactory Neuron Fates , 2001, Cell.

[66]  Thomas J. Nicholas,et al.  Automated analysis of embryonic gene expression with cellular resolution in C. elegans , 2008, Nature Methods.

[67]  J. Sulston,et al.  The Caenorhabditis elegans male: postembryonic development of nongonadal structures. , 1980, Developmental biology.

[68]  M. Chalfie,et al.  Regulation of touch receptor differentiation by the Caenorhabditis elegans mec-3 and unc-86 genes. , 1998, Development.

[69]  G. Ruvkun,et al.  Regulation of the mec‐3 gene by the C.elegans homeoproteins UNC‐86 and MEC‐3. , 1992, The EMBO journal.

[70]  O. Hobert.  The Impact of Whole Genome Sequencing on Model System Genetics: Get Ready for the Ride , 2010, Genetics.

[71]  G. Ruvkun,et al.  Detection of broadly expressed neuronal genes in C. elegans. , 2007, Developmental biology.

[72]  J. Thomas,et al.  The RFX-type transcription factor DAF-19 regulates sensory neuron cilium formation in C. elegans. , 2000, Molecular cell.

[73]  S. Hallam,et al.  The C. elegans NeuroD homolog cnd-1 functions in multiple aspects of motor neuron fate specification. , 2000, Development.

[74]  J. Hardin,et al.  Reciprocal asymmetry of SYS-1/β-catenin and POP-1/TCF controls asymmetric divisions in Caenorhabditis elegans , 2007, Proceedings of the National Academy of Sciences.

[75]  Steven J. M. Jones,et al.  The molecular signature and cis-regulatory architecture of a C. elegans gustatory neuron. , 2007, Genes & development.

[76]  A. R. Palmer,et al.  From symmetry to asymmetry: phylogenetic patterns of asymmetry variation in animals and their evolutionary significance. , 1996, Proceedings of the National Academy of Sciences of the United States of America.

[77]  T. Kaletta,et al.  Binary specification of the embryonic lineage in Caenorhabditis elegans , 1997, Nature.

[78]  R. Lin,et al.  POP-1 and Anterior–Posterior Fate Decisions in C. elegans Embryos , 1998, Cell.

[79]  Bret J. Pearson,et al.  The homeobox gene lim-6 is required for distinct chemosensory representations in C. elegans , 2001, Nature.

[80]  Oliver Hobert,et al.  MicroRNAs acting in a double-negative feedback loop to control a neuronal cell fate decision. , 2005, Proceedings of the National Academy of Sciences of the United States of America.

[81]  N. Munakata.  [Genetics of Caenorhabditis elegans]. , 1989, Tanpakushitsu kakusan koso. Protein, nucleic acid, enzyme.

[82]  H. Horvitz,et al.  Coordinated Transcriptional Regulation of the unc-25Glutamic Acid Decarboxylase and the unc-47 GABA Vesicular Transporter by the Caenorhabditis elegans UNC-30 Homeodomain Protein , 1999, The Journal of Neuroscience.

[83]  Kyuhyung Kim,et al.  Expression and regulation of an FMRFamide‐related neuropeptide gene family in Caenorhabditis elegans , 2004, The Journal of comparative neurology.

[84]  H. Horvitz,et al.  The lin-12 locus specifies cell fates in caenorhabditis elegans , 1983, Cell.

[85]  E. Hedgecock,et al.  Neuroglia and Pioneer Neurons Express UNC-6 to Provide Global and Local Netrin Cues for Guiding Migrations in C. elegans , 1996, Neuron.

[86]  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.

[87]  O. Hobert,et al.  Lineage programming: navigating through transient regulatory states via binary decisions. , 2010, Current opinion in genetics & development.

[88]  J. Sulston,et al.  The embryonic cell lineage of the nematode Caenorhabditis elegans. , 1983, Developmental biology.

[89]  I. Greenwald,et al.  LIN-12/Notch signaling: lessons from worms and flies. , 1998, Genes & development.

[90]  H. Sawa,et al.  Two betas or not two betas: regulation of asymmetric division by beta-catenin. , 2007, Trends in cell biology.

[91]  C. A. Frank,et al.  The Caenorhabditis elegans gene ham-2 links Hox patterning to migration of the HSN motor neuron. , 1999, Genes & development.

[92]  Oliver Hobert,et al.  Specification of the nervous system. , 2005, WormBook : the online review of C. elegans biology.

[93]  C. Kenyon,et al.  The role of lin-22, a hairy/enhancer of split homolog, in patterning the peripheral nervous system of C. elegans. , 1997, Development.

[94]  J. Modolell.  Patterning of the adult peripheral nervous system of Drosophila. , 1997, Perspectives on developmental neurobiology.

[95]  Y. Ohshima,et al.  The C. elegans che-1 gene encodes a zinc finger transcription factor required for specification of the ASE chemosensory neurons , 2003, Development.

[96]  Erik M. Jorgensen,et al.  The art and design of genetic screens: Caenorhabditis elegans , 2002, Nature Reviews Genetics.

[97]  B. Goldstein,et al.  The expression of the C. elegans labial-like Hox gene ceh-13 during early embryogenesis relies on cell fate and on anteroposterior cell polarity. , 1997, Development.

[98]  C. Mello,et al.  A CBP/p300 homolog specifies multiple differentiation pathways in Caenorhabditis elegans. , 1998, Genes & development.

[99]  Gary Ruvkun,et al.  Analysis of xbx genes in C. elegans , 2005, Development.

[100]  The Groucho ortholog UNC-37 interacts with the short Groucho-like protein LSY-22 to control developmental decisions in C. elegans , 2010, Development.

[101]  H. Horvitz,et al.  The C. elegans cell lineage and differentiation gene unc-86 encodes a protein with a homeodomain and extended similarity to transcription factors , 1988, Cell.

[102]  S. W. Emmons.  Male development. , 2005, WormBook : the online review of C. elegans biology.

[103]  C. Kenyon,et al.  Activation of a C. elegans Antennapedia homologue in migrating cells controls their direction of migration , 1992, Nature.

[104]  R. Schnabel,et al.  A Posterior Centre Establishes and Maintains Polarity of the Caenorhabditis elegans Embryo by a Wnt-Dependent Relay Mechanism , 2006, PLoS biology.

[105]  Andrew R. Gehrke,et al.  Transcriptional regulation and stabilization of left-right neuronal identity in C. elegans. , 2009, Genes & development.

[106]  H. Sawa,et al.  Two βs or not two βs: regulation of asymmetric division by β-catenin , 2007 .

[107]  J. Kimble,et al.  A new look at TCF and beta-catenin through the lens of a divergent C. elegans Wnt pathway. , 2009, Developmental cell.

[108]  P. Sengupta,et al.  The forkhead domain gene unc-130 generates chemosensory neuron diversity in C. elegans. , 2000, Genes & development.

[109]  C. Kenyon,et al.  Patterning C. elegans: homeotic cluster genes, cell fates and cell migrations. , 1994, Trends in genetics : TIG.

[110]  Martin Chalfie,et al.  Mutations that lead to reiterations in the cell lineages of C. elegans , 1981, Cell.

[111]  Gary Ruvkun,et al.  C. elegans unc-4 gene encodes a homeodomain protein that determines the pattern of synaptic input to specific motor neurons , 1992, Nature.

[112]  G. Ruvkun,et al.  Lineage-specific regulators couple cell lineage asymmetry to the transcription of the Caenorhabditis elegans POU gene unc-86 during neurogenesis. , 1996, Genes & development.

[113]  M. Chalfie,et al.  Cooperative interactions between the Caenorhabditis elegans homeoproteins UNC-86 and MEC-3. , 1993, Science.

[114]  Gary Ruvkun,et al.  The unc-86 gene product couples cell lineage and cell identity in C. elegans , 1990, Cell.

[115]  Oliver Hobert,et al.  A microRNA controlling left/right neuronal asymmetry in Caenorhabditis elegans , 2003, Nature.

[116]  Cornelia I. Bargmann,et al.  The C. elegans gene odr-7 encodes an olfactory-specific member of the nuclear receptor superfamily , 1994, Cell.

[117]  P. Sengupta,et al.  Specification of chemosensory neuron subtype identities in Caenorhabditis elegans , 2004, Current Opinion in Neurobiology.

[118]  O. Hobert,et al.  The lin-11 LIM homeobox gene specifies olfactory and chemosensory neuron fates in C. elegans. , 2001, Development.

[119]  E. Ricbaude.  Guanylyl cyclase expression in specific sensory neurons: A new family of chemosensory receptors , 1997 .

[120]  O. Hobert,et al.  Gene regulatory logic of dopaminergic neuron differentiation , 2009, Nature.

[121]  Linking asymmetric cell division to the terminal differentiation program of postmitotic neurons in C. elegans. , 2009, Developmental cell.

[122]  Oliver Hobert,et al.  Cis-regulatory mechanisms of left/right asymmetric neuron-subtype specification in C. elegans , 2009, Development.

[123]  R. L. Russell,et al.  Normal and mutant thermotaxis in the nematode Caenorhabditis elegans. , 1975, Proceedings of the National Academy of Sciences of the United States of America.