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Homeobox genes and the specification of neuronal identity

Abstract

The enormous diversity of cell types that characterizes any animal nervous system is defined by neuron-type-specific gene batteries that endow cells with distinct anatomical and functional properties. To understand how such cellular diversity is genetically specified, one needs to understand the gene regulatory programmes that control the expression of cell-type-specific gene batteries. The small nervous system of the nematode Caenorhabditis elegans has been comprehensively mapped at the cellular and molecular levels, which has enabled extensive, nervous system-wide explorations into whether there are common underlying mechanisms that specify neuronal cell-type diversity. One principle that emerged from these studies is that transcription factors termed ‘terminal selectors’ coordinate the expression of individual members of neuron-type-specific gene batteries, thereby assigning unique identities to individual neuron types. Systematic mutant analyses and recent nervous system-wide expression analyses have revealed that one transcription factor family, the homeobox gene family, is broadly used throughout the entire C. elegans nervous system to specify neuronal identity as terminal selectors. I propose that the preponderance of homeobox genes in neuronal identity control is a reflection of an evolutionary trajectory in which an ancestral neuron type was specified by one or more ancestral homeobox genes, and that this functional linkage then duplicated and diversified to generate distinct cell types in an evolving nervous system.

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Fig. 1: Homeobox gene complement in some model animal genomes.
Fig. 2: Models for the regulation of neuron-type-specific gene batteries by transcription factors.
Fig. 3: Homeobox gene expression in the nervous system of Caenorhabditis elegans.
Fig. 4: Terminal selectors in Caenorhabditis elegans.
Fig. 5: A hypothetical scenario for the individuation of two sister neurons.

References

  1. 1.

    y Cajal, R. Histologie du Système Nerveux de L’homme et des Vertébrés (Maloine, 1911).

  2. 2.

    Bota, M. & Swanson, L. W. The neuron classification problem. Brain Res. Rev. 56, 79–88 (2007).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  3. 3.

    Zeng, H. & Sanes, J. R. Neuronal cell-type classification: challenges, opportunities and the path forward. Nat. Rev. Neurosci. 18, 530–546 (2017).

    CAS  PubMed  Article  Google Scholar 

  4. 4.

    Tasic, B. Single cell transcriptomics in neuroscience: cell classification and beyond. Curr. Opin. Neurobiol. 50, 242–249 (2018).

    CAS  PubMed  Article  Google Scholar 

  5. 5.

    Arendt, D. et al. The origin and evolution of cell types. Nat. Rev. Genet. 17, 744–757 (2016).

    CAS  PubMed  Article  Google Scholar 

  6. 6.

    Burglin, T. R. & Affolter, M. Homeodomain proteins: an update. Chromosoma 125, 497–521 (2016).

    CAS  PubMed  Article  Google Scholar 

  7. 7.

    Gehring, W. J. Master Control Genes in Development and Evolution: The Homeobox Story (Yale Univ. Press, 1998).

  8. 8.

    McGinnis, W., Levine, M. S., Hafen, E., Kuroiwa, A. & Gehring, W. J. A conserved DNA sequence in homoeotic genes of the Drosophila Antennapedia and bithorax complexes. Nature 308, 428–433 (1984).

    CAS  PubMed  Article  Google Scholar 

  9. 9.

    Scott, M. P. & Weiner, A. J. Structural relationships among genes that control development: sequence homology between the Antennapedia, Ultrabithorax, and fushi tarazu loci of Drosophila. Proc. Natl Acad. Sci. USA 81, 4115–4119 (1984).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  10. 10.

    Lewis, E. B. A gene complex controlling segmentation in Drosophila. Nature 276, 565–570 (1978).

    CAS  PubMed  Article  Google Scholar 

  11. 11.

    Carrasco, A. E., McGinnis, W., Gehring, W. J. & De Robertis, E. M. Cloning of an X. laevis gene expressed during early embryogenesis coding for a peptide region homologous to Drosophila homeotic genes. Cell 37, 409–414 (1984).

    CAS  PubMed  Article  Google Scholar 

  12. 12.

    McGinnis, W., Garber, R. L., Wirz, J., Kuroiwa, A. & Gehring, W. J. A homologous protein-coding sequence in Drosophila homeotic genes and its conservation in other metazoans. Cell 37, 403–408 (1984).

    CAS  PubMed  Article  Google Scholar 

  13. 13.

    Burglin, T. R., Finney, M., Coulson, A. & Ruvkun, G. Caenorhabditis elegans has scores of homoeobox-containing genes. Nature 341, 239–243 (1989).

    CAS  PubMed  Article  Google Scholar 

  14. 14.

    Vaquerizas, J. M., Kummerfeld, S. K., Teichmann, S. A. & Luscombe, N. M. A census of human transcription factors: function, expression and evolution. Nat. Rev. Genet. 10, 252–263 (2009).

    CAS  PubMed  Article  Google Scholar 

  15. 15.

    Derelle, R., Lopez, P., Le Guyader, H. & Manuel, M. Homeodomain proteins belong to the ancestral molecular toolkit of eukaryotes. Evol. Dev. 9, 212–219 (2007).

    CAS  PubMed  Article  Google Scholar 

  16. 16.

    Holland, P. W. Evolution of homeobox genes. Wiley Interdiscip. Rev. Dev. Biol. 2, 31–45 (2013).

    CAS  PubMed  Article  Google Scholar 

  17. 17.

    Garcia-Fernandez, J. The genesis and evolution of homeobox gene clusters. Nat. Rev. Genet. 6, 881–892 (2005).

    CAS  PubMed  Article  Google Scholar 

  18. 18.

    Ryan, J. F. et al. The cnidarian-bilaterian ancestor possessed at least 56 homeoboxes: evidence from the starlet sea anemone, Nematostella vectensis. Genome Biol. 7, R64 (2006).

    PubMed  PubMed Central  Article  CAS  Google Scholar 

  19. 19.

    Blochlinger, K., Bodmer, R., Jack, J., Jan, L. Y. & Jan, Y. N. Primary structure and expression of a product from cut, a locus involved in specifying sensory organ identity in Drosophila. Nature 333, 629–635 (1988).

    CAS  PubMed  Article  Google Scholar 

  20. 20.

    Doe, C. Q., Hiromi, Y., Gehring, W. J. & Goodman, C. S. Expression and function of the segmentation gene fushi tarazu during Drosophila neurogenesis. Science 239, 170–175 (1988).

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  21. 21.

    Doe, C. Q., Smouse, D. & Goodman, C. S. Control of neuronal fate by the Drosophila segmentation gene even-skipped. Nature 333, 376–378 (1988).

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  22. 22.

    Brenner, S. The genetics of Caenorhabditis elegans. Genetics 77, 71–94 (1974).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  23. 23.

    Hedgecock, E. M. & Russell, R. L. Normal and mutant thermotaxis in the nematode Caenorhabditis elegans. Proc. Natl Acad. Sci. USA 72, 4061–4065 (1975).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  24. 24.

    Chalfie, M. & Sulston, J. Developmental genetics of the mechanosensory neurons of Caenorhabditis elegans. Dev. Biol. 82, 358–370 (1981).

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  25. 25.

    Finney, M., Ruvkun, G. & Horvitz, H. R. The C. elegans cell lineage and differentiation gene unc-86 encodes a protein with a homeodomain and extended similarity to transcription factors. Cell 55, 757–769 (1988).

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  26. 26.

    Way, J. C. & Chalfie, M. mec-3, a homeobox-containing gene that specifies differentiation of the touch receptor neurons in C. elegans. Cell 54, 5–16 (1988).

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  27. 27.

    Miller, D. M. et al. C. elegans unc-4 gene encodes a homeodomain protein that determines the pattern of synaptic input to specific motor neurons. Nature 355, 841–845 (1992).

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  28. 28.

    Jin, Y., Hoskins, R. & Horvitz, H. R. Control of type-D GABAergic neuron differentiation by C. elegans UNC-30 homeodomain protein. Nature 372, 780–783 (1994).

    CAS  PubMed  Article  Google Scholar 

  29. 29.

    Baran, R., Aronoff, R. & Garriga, G. The C. elegans homeodomain gene unc-42 regulates chemosensory and glutamate receptor expression. Development 126, 2241–2251 (1999).

    CAS  PubMed  Article  Google Scholar 

  30. 30.

    Satterlee, J. S. et al. Specification of thermosensory neuron fate in C. elegans requires ttx-1, a homolog of otd/Otx. Neuron 31, 943–956 (2001).

    CAS  PubMed  Article  Google Scholar 

  31. 31.

    Hobert, O. et al. Regulation of interneuron function in the C. elegans thermoregulatory pathway by the ttx-3 LIM homeobox gene. Neuron 19, 345–357 (1997).

    CAS  PubMed  Article  Google Scholar 

  32. 32.

    Rubenstein, J. L. & Puelles, L. Homeobox gene expression during development of the vertebrate brain. Curr. Top. Dev. Biol. 29, 1–63 (1994).

    CAS  PubMed  Article  Google Scholar 

  33. 33.

    Tsuchida, T. et al. Topographic organization of embryonic motor neurons defined by expression of LIM homeobox genes. Cell 79, 957–970 (1994).

    CAS  PubMed  Article  Google Scholar 

  34. 34.

    Joyner, A. L., Herrup, K., Auerbach, B. A., Davis, C. A. & Rossant, J. Subtle cerebellar phenotype in mice homozygous for a targeted deletion of the En-2 homeobox. Science 251, 1239–1243 (1991).

    CAS  PubMed  Article  Google Scholar 

  35. 35.

    Qiu, M. et al. Null mutation of Dlx-2 results in abnormal morphogenesis of proximal first and second branchial arch derivatives and abnormal differentiation in the forebrain. Genes Dev. 9, 2523–2538 (1995).

    CAS  PubMed  Article  Google Scholar 

  36. 36.

    Pfaff, S. L., Mendelsohn, M., Stewart, C. L., Edlund, T. & Jessell, T. M. Requirement for LIM homeobox gene Isl1 in motor neuron generation reveals a motor neuron-dependent step in interneuron differentiation. Cell 84, 309–320 (1996).

    CAS  PubMed  Article  Google Scholar 

  37. 37.

    Hobert, O. & Westphal, H. Function of LIM homeobox genes. Trends Genet. 16, 75–83 (2000).

    CAS  PubMed  Article  Google Scholar 

  38. 38.

    McIntire, S. L., Jorgensen, E. & Horvitz, H. R. Genes required for GABA function in Caenorhabditis elegans. Nature 364, 334–337 (1993).

    CAS  PubMed  Article  Google Scholar 

  39. 39.

    Mori, I. & Ohshima, Y. Neural regulation of thermotaxis in Caenorhabditis elegans. Nature 376, 344–348 (1995).

    CAS  PubMed  Article  Google Scholar 

  40. 40.

    Way, J. C. & Chalfie, M. The mec-3 gene of Caenorhabditis elegans requires its own product for maintained expression and is expressed in three neuronal cell types. Genes Dev. 3, 1823–1833 (1989).

    CAS  PubMed  Article  Google Scholar 

  41. 41.

    Hobert, O. A map of terminal regulators of neuronal identity in Caenorhabditis elegans. Wiley Interdiscip. Rev. Dev. Biol. 5, 474–498 (2016).

    PubMed  PubMed Central  Article  Google Scholar 

  42. 42.

    Hobert, O., Glenwinkel, L. & White, J. Revisiting neuronal cell type classification in Caenorhabditis elegans. Curr. Biol. 26, R1197–R1203 (2016).

    CAS  PubMed  Article  Google Scholar 

  43. 43.

    Zhang, Y. et al. Identification of genes expressed in C. elegans touch receptor neurons. Nature 418, 331–335 (2002).

    CAS  PubMed  Article  Google Scholar 

  44. 44.

    Duggan, A., Ma, C. & Chalfie, M. Regulation of touch receptor differentiation by the Caenorhabditis elegans mec-3 and unc-86 genes. Development 125, 4107–4119 (1998).

    CAS  PubMed  Article  Google Scholar 

  45. 45.

    Eastman, C., Horvitz, H. R. & Jin, Y. Coordinated transcriptional regulation of the unc-25 glutamic acid decarboxylase and the unc-47 GABA vesicular transporter by the Caenorhabditis elegans UNC-30 homeodomain protein. J. Neurosci. 19, 6225–6234 (1999).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  46. 46.

    Cinar, H., Keles, S. & Jin, Y. Expression profiling of GABAergic motor neurons in Caenorhabditis elegans. Curr. Biol. 15, 340–346 (2005).

    CAS  PubMed  Article  Google Scholar 

  47. 47.

    Yu, B. et al. Convergent transcriptional programs regulate cAMP levels in C. elegans GABAergic motor neurons. Dev. Cell 43, 212–226.e7 (2017).

    CAS  PubMed  Article  Google Scholar 

  48. 48.

    Wenick, A. S. & Hobert, O. Genomic cis-regulatory architecture and trans-acting regulators of a single interneuron-specific gene battery in C. elegans. Dev. Cell 6, 757–770 (2004).

    CAS  PubMed  Article  Google Scholar 

  49. 49.

    Alqadah, A. et al. Postmitotic diversification of olfactory neuron types is mediated by differential activities of the HMG-box transcription factor SOX-2. EMBO J. 34, 2574–2589 (2015).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  50. 50.

    Lanjuin, A., VanHoven, M. K., Bargmann, C. I., Thompson, J. K. & Sengupta, P. Otx/otd homeobox genes specify distinct sensory neuron identities in C. elegans. Dev. Cell 5, 621–633 (2003).

    CAS  PubMed  Article  Google Scholar 

  51. 51.

    Hobert, O. Regulatory logic of neuronal diversity: terminal selector genes and selector motifs. Proc. Natl Acad. Sci. USA 105, 20067–20071 (2008).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  52. 52.

    Hobert, O. Regulation of terminal differentiation programs in the nervous system. Annu. Rev. Cell Dev. Biol. 27, 681–696 (2011).

    CAS  PubMed  Article  Google Scholar 

  53. 53.

    Hobert, O. Terminal selectors of neuronal identity. Curr. Top. Dev. Biol. 116, 455–475 (2016).

    CAS  PubMed  Article  Google Scholar 

  54. 54.

    Glenwinkel, L. et al. In silico analysis of the transcriptional regulatory logic of neuronal identity specification throughout the C. elegans nervous system. eLife 10, e64906 (2021).

    PubMed  PubMed Central  Article  Google Scholar 

  55. 55.

    Xue, D., Tu, Y. & Chalfie, M. Cooperative interactions between the Caenorhabditis elegans homeoproteins UNC-86 and MEC-3. Science 261, 1324–1328 (1993).

    CAS  PubMed  Article  Google Scholar 

  56. 56.

    Leyva-Diaz, E., Masoudi, N., Serrano-Saiz, E., Glenwinkel, L. & Hobert, O. Brn3/POU-IV-type POU homeobox genes — paradigmatic regulators of neuronal identity across phylogeny. Wiley Interdiscip Rev. Dev. Biol. 9, e374 (2020).

    CAS  PubMed  Article  Google Scholar 

  57. 57.

    Gordon, P. M. & Hobert, O. A competition mechanism for a homeotic neuron identity transformation in C. elegans. Dev. Cell 34, 206–219 (2015).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  58. 58.

    Serrano-Saiz, E. et al. Modular control of glutamatergic neuronal identity in C. elegans by distinct homeodomain proteins. Cell 155, 659–673 (2013).

    CAS  PubMed  Article  Google Scholar 

  59. 59.

    Serrano-Saiz, E., Oren-Suissa, M., Bayer, E. A. & Hobert, O. Sexually dimorphic differentiation of a C. elegans hub neuron is cell autonomously controlled by a conserved transcription factor. Curr. Biol. 27, 199–209 (2017).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  60. 60.

    Zhang, F. et al. The LIM and POU homeobox genes ttx-3 and unc-86 act as terminal selectors in distinct cholinergic and serotonergic neuron types. Development 141, 422–435 (2014).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  61. 61.

    Lloret-Fernandez, C. et al. A transcription factor collective defines the HSN serotonergic neuron regulatory landscape. eLife 7, e32785 (2018).

    PubMed  PubMed Central  Article  Google Scholar 

  62. 62.

    Levine, M. & Tjian, R. Transcription regulation and animal diversity. Nature 424, 147–151 (2003).

    CAS  PubMed  Article  Google Scholar 

  63. 63.

    Junion, G. et al. A transcription factor collective defines cardiac cell fate and reflects lineage history. Cell 148, 473–486 (2012).

    CAS  PubMed  Article  Google Scholar 

  64. 64.

    Doitsidou, M. et al. A combinatorial regulatory signature controls terminal differentiation of the dopaminergic nervous system in C. elegans. Genes Dev. 27, 1391–1405 (2013).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  65. 65.

    White, J. G., Southgate, E., Thomson, J. N. & Brenner, S. The structure of the nervous system of the nematode Caenorhabditis elegans. Philos. Trans. R. Soc. Lond. B Biol. Sci. 314, 1–340 (1986).

    CAS  PubMed  Article  Google Scholar 

  66. 66.

    Cook, S. J. et al. Whole-animal connectomes of both Caenorhabditis elegans sexes. Nature 571, 63–71 (2019).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  67. 67.

    Taylor, S. R. et al. Molecular topography of an entire nervous system. Cell 184, 4329–4347.e23 (2021).

    CAS  PubMed  Article  Google Scholar 

  68. 68.

    Hench, J. et al. The homeobox genes of Caenorhabditis elegans and insights into their spatio-temporal expression dynamics during embryogenesis. PLoS ONE 10, e0126947 (2015).

    PubMed  PubMed Central  Article  CAS  Google Scholar 

  69. 69.

    Reilly, M. B., Cros, C., Varol, E., Yemini, E. & Hobert, O. Unique homeobox codes delineate all the neuron classes of C. elegans. Nature 584, 595–601 (2020).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  70. 70.

    Arendt, D., Bertucci, P. Y., Achim, K. & Musser, J. M. Evolution of neuronal types and families. Curr. Opin. Neurobiol. 56, 144–152 (2019).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  71. 71.

    Zeisel, A. et al. Molecular architecture of the mouse nervous system. Cell 174, 999–1014.e22 (2018).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  72. 72.

    Davis, F. P. et al. A genetic, genomic, and computational resource for exploring neural circuit function. eLife 9, e50901 (2020).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  73. 73.

    Sugino, K. et al. Mapping the transcriptional diversity of genetically and anatomically defined cell populations in the mouse brain. eLife 8, e38619 (2019).

    PubMed  PubMed Central  Article  Google Scholar 

  74. 74.

    Sagasti, A., Hobert, O., Troemel, E. R., Ruvkun, G. & Bargmann, C. I. Alternative olfactory neuron fates are specified by the LIM homeobox gene lim-4. Genes Dev. 13, 1794–1806 (1999).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  75. 75.

    O’Keefe, D. D., Thor, S. & Thomas, J. B. Function and specificity of LIM domains in Drosophila nervous system and wing development. Development 125, 3915–3923 (1998).

    PubMed  Article  Google Scholar 

  76. 76.

    Thor, S. & Thomas, J. B. The Drosophila islet gene governs axon pathfinding and neurotransmitter identity. Neuron 18, 397–409 (1997).

    CAS  PubMed  Article  Google Scholar 

  77. 77.

    Swaroop, A., Kim, D. & Forrest, D. Transcriptional regulation of photoreceptor development and homeostasis in the mammalian retina. Nat. Rev. Neurosci. 11, 563–576 (2010).

    CAS  PubMed  Article  Google Scholar 

  78. 78.

    Zhang, G., Titlow, W. B., Biecker, S. M., Stromberg, A. J. & McClintock, T. S. Lhx2 determines odorant receptor expression frequency in mature olfactory sensory neurons. eNeuro 3, ENEURO.0230-16.2016 (2016).

  79. 79.

    Monahan, K. et al. Cooperative interactions enable singular olfactory receptor expression in mouse olfactory neurons. eLife 6, e28620 (2017).

    PubMed  PubMed Central  Article  Google Scholar 

  80. 80.

    Pla, R. et al. Dlx1 and Dlx2 promote interneuron GABA synthesis, synaptogenesis, and dendritogenesis. Cereb. Cortex 28, 3797–3815 (2018).

    PubMed  Article  Google Scholar 

  81. 81.

    Lindtner, S. et al. Genomic resolution of DLX-orchestrated transcriptional circuits driving development of forebrain GABAergic neurons. Cell Rep. 28, 2048–2063.e8 (2019).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  82. 82.

    Smidt, M. P. & Burbach, J. P. Terminal differentiation of mesodiencephalic dopaminergic neurons: the role of Nurr1 and Pitx3. Adv. Exp. Med. Biol. 651, 47–57 (2009).

    CAS  PubMed  Article  Google Scholar 

  83. 83.

    Kratsios, P., Stolfi, A., Levine, M. & Hobert, O. Coordinated regulation of cholinergic motor neuron traits through a conserved terminal selector gene. Nat. Neurosci. 15, 205–214 (2011).

    PubMed  PubMed Central  Article  CAS  Google Scholar 

  84. 84.

    White, J. G., Southgate, E. & Thomson, J. N. Mutations in the Caenorhabditis elegans unc-4 gene alter the synaptic input to ventral cord motor neurons. Nature 355, 838–841 (1992).

    CAS  PubMed  Article  Google Scholar 

  85. 85.

    Winnier, A. R. et al. UNC-4/UNC-37-dependent repression of motor neuron-specific genes controls synaptic choice in Caenorhabditis elegans. Genes Dev. 13, 2774–2786 (1999).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  86. 86.

    Von Stetina, S. E. et al. UNC-4 represses CEH-12/HB9 to specify synaptic inputs to VA motor neurons in C. elegans. Genes Dev. 21, 332–346 (2007).

    Article  CAS  Google Scholar 

  87. 87.

    Kerk, S. Y., Kratsios, P., Hart, M., Mourao, R. & Hobert, O. Diversification of C. elegans motor neuron identity via selective effector gene repression. Neuron 93, 80–98 (2017).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  88. 88.

    Esmaeili, B., Ross, J. M., Neades, C., Miller, D. M. 3rd & Ahringer, J. The C. elegans even-skipped homologue, vab-7, specifies DB motoneurone identity and axon trajectory. Development 129, 853–862 (2002).

    CAS  PubMed  Article  Google Scholar 

  89. 89.

    Petersen, S. C. et al. A transcriptional program promotes remodeling of GABAergic synapses in Caenorhabditis elegans. J. Neurosci. 31, 15362–15375 (2011).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  90. 90.

    Hsieh, Y. W., Alqadah, A. & Chuang, C. F. Asymmetric neural development in the Caenorhabditis elegans olfactory system. Genesis 52, 544–554 (2014).

    PubMed  PubMed Central  Article  Google Scholar 

  91. 91.

    Hobert, O. Development of left/right asymmetry in the Caenorhabditis elegans nervous system: from zygote to postmitotic neuron. Genesis 52, 528–543 (2014).

    PubMed  Article  Google Scholar 

  92. 92.

    Feng, W. et al. A terminal selector prevents a Hox transcriptional switch to safeguard motor neuron identity throughout life. Preprint at bioRxiv https://doi.org/10.1101/643320 (2019).

    Article  Google Scholar 

  93. 93.

    Kratsios, P. et al. An intersectional gene regulatory strategy defines subclass diversity of C. elegans motor neurons. eLife 6, e25751 (2017).

    PubMed  PubMed Central  Article  Google Scholar 

  94. 94.

    Dasen, J. S. & Jessell, T. M. Hox networks and the origins of motor neuron diversity. Curr. Top. Dev. Biol. 88, 169–200 (2009).

    CAS  PubMed  Article  Google Scholar 

  95. 95.

    Jung, H. et al. The ancient origins of neural substrates for land walking. Cell 172, 667–682.e15 (2018).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  96. 96.

    Zheng, C., Diaz-Cuadros, M. & Chalfie, M. Hox genes promote neuronal subtype diversification through posterior induction in Caenorhabditis elegans. Neuron 88, 514–527 (2015).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  97. 97.

    Flames, N. & Hobert, O. Gene regulatory logic of dopamine neuron differentiation. Nature 458, 885–889 (2009).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  98. 98.

    Vidal, B. et al. C. elegans SoxB genes are dispensable for embryonic neurogenesis but required for terminal differentiation of specific neuron types. Development 142, 2464–2477 (2015).

    CAS  PubMed  PubMed Central  Google Scholar 

  99. 99.

    Berghoff, E. et al. The Prop1-like homeobox gene unc-42 specifies the identity of synaptically connected neurons. eLife 10, e64903 (2021).

    PubMed  PubMed Central  Article  Google Scholar 

  100. 100.

    Pereira, L. et al. A cellular and regulatory map of the cholinergic nervous system of C. elegans. eLife 4, e12432 (2015).

    PubMed  PubMed Central  Article  Google Scholar 

  101. 101.

    Dobzhansky, T. Biology, molecular and organismic. Am. Zool. 4, 443–452 (1964).

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  102. 102.

    Arendt, D. The evolutionary assembly of neuronal machinery. Curr. Biol. 30, R603–R616 (2020).

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  103. 103.

    Achim, K. & Arendt, D. Structural evolution of cell types by step-wise assembly of cellular modules. Curr. Opin. Genet. Dev. 27, 102–108 (2014).

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  104. 104.

    Arendt, D. Elementary nervous systems. Phil. Trans. R. Soc. B 376, 20200347 (2021).

    PubMed  PubMed Central  Article  Google Scholar 

  105. 105.

    Holland, P. W. Did homeobox gene duplications contribute to the Cambrian explosion? Zool. Lett. 1, 1 (2015).

    Article  Google Scholar 

  106. 106.

    Akam, M. Hox genes, homeosis and the evolution of segment identity: no need for hopeless monsters. Int. J. Dev. Biol. 42, 445–451 (1998).

    CAS  PubMed  PubMed Central  Google Scholar 

  107. 107.

    Arlotta, P. & Hobert, O. Homeotic transformations of neuronal cell identities. Trends Neurosci. 38, 751–762 (2015).

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  108. 108.

    Bateson, W. Materials for the Study of Variation, Treated with Especial Regard to Discontinuity in the Origin of Species (Macmillan, 1894).

  109. 109.

    Sattler, R. Homeosis in plants. Am. J. Bot. 75, 1606–1617 (1988).

    Article  Google Scholar 

  110. 110.

    Wagner, G. P. Homology, Genes and Evolutionary Innovation (Princeton Univ. Press, 2014).

  111. 111.

    Tosches, M. A. Developmental and genetic mechanisms of neural circuit evolution. Dev. Biol. 431, 16–25 (2017).

    CAS  PubMed  Article  Google Scholar 

  112. 112.

    Velten, J. et al. The molecular logic of synaptic wiring at the single cell level. Preprint at bioRxiv https://doi.org/10.1101/2020.11.30.402057 (2021).

    Article  Google Scholar 

  113. 113.

    Dauger, S. et al. Phox2b controls the development of peripheral chemoreceptors and afferent visceral pathways. Development 130, 6635–6642 (2003).

    CAS  PubMed  Article  Google Scholar 

  114. 114.

    Shin, M. M., Catela, C. & Dasen, J. Intrinsic control of neuronal diversity and synaptic specificity in a proprioceptive circuit. eLife 9, e56374 (2020).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  115. 115.

    Ha, N. T. & Dougherty, K. J. Spinal Shox2 interneuron interconnectivity related to function and development. eLife 7, e42519 (2018).

    PubMed  PubMed Central  Article  Google Scholar 

  116. 116.

    Ruiz-Reig, N. et al. Developmental requirement of homeoprotein Otx2 for specific habenulo-interpeduncular subcircuits. J. Neurosci. 39, 1005–1019 (2019).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  117. 117.

    Parker, H. J. & Krumlauf, R. A Hox gene regulatory network for hindbrain segmentation. Curr. Top. Dev. Biol. 139, 169–203 (2020).

    CAS  PubMed  Article  Google Scholar 

  118. 118.

    Zheng, C., Jin, F. Q. & Chalfie, M. Hox proteins act as transcriptional guarantors to ensure terminal differentiation. Cell Rep. 13, 1343–1352 (2015).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  119. 119.

    Urbach, R. & Technau, G. M. Dorsoventral patterning of the brain: a comparative approach. Adv. Exp. Med. Biol. 628, 42–56 (2008).

    PubMed  Article  Google Scholar 

  120. 120.

    Briscoe, J., Pierani, A., Jessell, T. M. & Ericson, J. A homeodomain protein code specifies progenitor cell identity and neuronal fate in the ventral neural tube. Cell 101, 435–445 (2000).

    CAS  PubMed  Article  Google Scholar 

  121. 121.

    Zhang, Q. & Eisenstat, D. D. Roles of homeobox genes in retinal ganglion cell differentiation and axonal guidance. Adv. Exp. Med. Biol. 723, 685–691 (2012).

    CAS  PubMed  Article  Google Scholar 

  122. 122.

    Lichtneckert, R. & Reichert, H. Anteroposterior regionalization of the brain: genetic and comparative aspects. Adv. Exp. Med. Biol. 628, 32–41 (2008).

    PubMed  Article  Google Scholar 

  123. 123.

    Serrano-Saiz, E., Leyva-Diaz, E., De La Cruz, E. & Hobert, O. BRN3-type POU homeobox genes maintain the identity of mature postmitotic neurons in nematodes and mice. Curr. Biol. 28, 2813–2823.e2 (2018).

    CAS  PubMed  Article  Google Scholar 

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Acknowledgements

The author thanks M. Reilly for help with the figures, M. Tosches, T. Bürglin, P. Kratsios and the current members of his laboratory for comments on the manuscript and the Howard Hughes Medical Institute for funding.

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Nature Reviews Neuroscience thanks K. Lee, who co-reviewed with C. Doe, and the other, anonymous, reviewer(s) for their contribution to the peer review of this work.

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Hobert, O. Homeobox genes and the specification of neuronal identity. Nat Rev Neurosci 22, 627–636 (2021). https://doi.org/10.1038/s41583-021-00497-x

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