Abstract
Species are endowed with unique sensory capabilities that are encoded by divergent neural circuits. One potential explanation for how divergent circuits have evolved is that conserved extrinsic signals are differentially interpreted by developing neurons of different species to yield unique patterns of axonal connections. Although nerve growth factor (NGF) controls survival, maturation and axonal projections of nociceptors of different vertebrates, whether the NGF signal is differentially transduced in different species to yield unique features of nociceptor circuits is unclear. We identified a species-specific signaling module induced by NGF and mediated by a rapidly evolving Hox transcription factor, Hoxd1. NGF promoted robust expression of Hoxd1 in mice, but not chickens, both in vivo and in vitro. Mice lacking Hoxd1 displayed altered nociceptor circuitry that resembles that normally found in chicks. Conversely, ectopic expression of Hoxd1 in developing chick nociceptors promoted a pattern of axonal projections reminiscent of the mouse. Thus, conserved growth factors control divergent neuronal transcriptional events that mediate interspecies differences in neural circuits and the behaviors that they control.
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References
Dodd, J. & Jessell, T.M. Axon guidance and the patterning of neuronal projections in vertebrates. Science 242, 692–699 (1988).
Tessier-Lavigne, M. & Goodman, C.S. The molecular biology of axon guidance. Science 274, 1123–1133 (1996).
Huber, A.B., Kolodkin, A.L., Ginty, D.D. & Cloutier, J.F. Signaling at the growth cone: ligand-receptor complexes and the control of axon growth and guidance. Annu. Rev. Neurosci. 26, 509–563 (2003).
Snider, W.D. Functions of the neurotrophins during nervous system development: what the knockouts are teaching us. Cell 77, 627–638 (1994).
Huang, E.J. & Reichardt, L.F. Neurotrophins: roles in neuronal development and function. Annu. Rev. Neurosci. 24, 677–736 (2001).
Levi-Montalcini, R. The nerve growth factor 35 years later. Science 237, 1154–1162 (1987).
Gundersen, R.W. & Barrett, J.N. Neuronal chemotaxis: chick dorsal-root axons turn toward high concentrations of nerve growth factor. Science 206, 1079–1080 (1979).
Mirnics, K. & Koerber, H.R. Prenatal development of rat primary afferent fibers. II. Central projections. J. Comp. Neurol. 355, 601–614 (1995).
Eide, A.L. & Glover, J.C. Developmental dynamics of functionally specific primary sensory afferent projections in the chicken embryo. Anat. Embryol. (Berl.) 195, 237–250 (1997).
Rice, F.L. & Albrecht, P.J. Cutaneous mechanisms of tactile perception: morphological and chemical organization of the innervation to the skin. in The Senses: a Comprehensive Reference, Vol. 6 (eds Basbaum, A.I., Kaneko, A., Shepherd, G.M. & Westheimer, G.) 1–32 (Academic Press, New York, 2008).
Zylka, M.J., Rice, F.L. & Anderson, D.J. Topographically distinct epidermal nociceptive circuits revealed by axonal tracers targeted to Mrgprd. Neuron 45, 17–25 (2005).
Lucas, A.M. & Stettenheim, P.R. Avian Anatomy: Integument, Vol. 2 (United States Department of Agriculture, Washington, D.C., 1972).
Hemming, F.J., Pays, L., Soubeyran, A., Larruat, C. & Saxod, R. Development of sensory innervation in chick skin: comparison of nerve fibre and chondroitin sulphate distributions in vivo and in vitro. Cell Tissue Res. 277, 519–529 (1994).
Von During, M. & Miller, M.L. Sensory nerve endings of the skin and deeper structures. in Biology of the Reptilia, Vol. 9 (ed. Gans, C.) 407–441 (Academic Press, New York, 1979).
Chuong, C.M., Chodankar, R., Widelitz, R.B. & Jiang, T.X. Evo-devo of feathers and scales: building complex epithelial appendages. Curr. Opin. Genet. Dev. 10, 449–456 (2000).
Wu, P. et al. Evo-Devo of amniote integuments and appendages. Int. J. Dev. Biol. 48, 249–270 (2004).
Chang, C. et al. Reptile scale paradigm: Evo-Devo, pattern formation and regeneration. Int. J. Dev. Biol. 53, 813–826 (2009).
Mandai, K. et al. LIG family receptor tyrosine kinase-associated proteins modulate growth factor signals during neural development. Neuron 63, 614–627 (2009).
Patel, T.D., Jackman, A., Rice, F.L., Kucera, J. & Snider, W.D. Development of sensory neurons in the absence of NGF/TrkA signaling in vivo. Neuron 25, 345–357 (2000).
Pearson, J.C., Lemons, D. & McGinnis, W. Modulating Hox gene functions during animal body patterning. Nat. Rev. Genet. 6, 893–904 (2005).
Tvrdik, P. & Capecchi, M.R. Reversal of Hox1 gene subfunctionalization in the mouse. Dev. Cell 11, 239–250 (2006).
Frohman, M.A. & Martin, G.R. Isolation and analysis of embryonic expression of Hox-4.9, a member of the murine labial-like gene family. Mech. Dev. 38, 55–67 (1992).
Kolm, P.J. & Sive, H.L. Regulation of the Xenopus labial homeodomain genes, HoxA1 and HoxD1: activation by retinoids and peptide growth factors. Dev. Biol. 167, 34–49 (1995).
Liu, Q. et al. Molecular genetic visualization of a rare subset of unmyelinated sensory neurons that may detect gentle touch. Nat. Neurosci. 10, 946–948 (2007).
Saxod, R. Development of cutaneous sensory receptors in birds. in Handbook of Sensory Physiology, Vol. IX: Development of Sensory Systems (ed. Jacobson, M.) 338 (Springer-Verlag, Berlin, 1978).
Wall, P.D., Kerr, B.J. & Ramer, M.S. Primary afferent input to and receptive field properties of cells in rat lumbar area X. J. Comp. Neurol. 449, 298–306 (2002).
Honda, C.N. Visceral and somatic afferent convergence onto neurons near the central canal in the sacral spinal cord of the cat. J. Neurophysiol. 53, 1059–1078 (1985).
Nadelhaft, I., Roppolo, J., Morgan, C. & de Groat, W.C. Parasympathetic preganglionic neurons and visceral primary afferents in monkey sacral spinal cord revealed following application of horseradish peroxidase to pelvic nerve. J. Comp. Neurol. 216, 36–52 (1983).
Chung, K., Lee, W.T. & Park, M.J. Spinal projections of pelvic visceral afferents of the rat: a calcitonin gene-related peptide (CGRP) immunohistochemical study. J. Comp. Neurol. 337, 63–69 (1993).
Martínez-García, F., Novejarque, A., Landete, J.M., Moncho-Bogani, J. & Lanuza, E. Distribution of calcitonin gene-related peptide-like immunoreactivity in the brain of the lizard Podarcis hispanica. J. Comp. Neurol. 447, 99–113 (2002).
Werner, T., Hammer, A., Wahlbuhl, M., Bosl, M.R. & Wegner, M. Multiple conserved regulatory elements with overlapping functions determine Sox10 expression in mouse embryogenesis. Nucleic Acids Res. 35, 6526–6538 (2007).
Chen, A.I., de Nooij, J.C. & Jessell, T.M. Graded activity of transcription factor Runx3 specifies the laminar termination pattern of sensory axons in the developing spinal cord. Neuron 49, 395–408 (2006).
Kemp, T.S. The Origin and Evolution of Mammals (Oxford University Press, Oxford, 2005).
Kardong, K.V. Vertebrates: Comparative Anatomy, Function, Evolution (McGraw-Hill Higher Education, 2006).
Zanazzi, A., Kohn, M.J., MacFadden, B.J. & Terry, D.O. Large temperature drop across the Eocene-Oligocene transition in central North America. Nature 445, 639–642 (2007).
Prothero, D.R. & Berggren, W.A. Eocene-Oligocene Climatic and Biotic Evolution (Princeton University Press, Princeton, New Jersey, 1992).
Kim, S.J., Qu, Z., Milbrandt, J. & Zhuo, M. A transcription factor for cold sensation!. Mol. Pain 1, 11 (2005).
Luo, W. et al. A hierarchical NGF signaling cascade controls Ret-dependent and Ret-independent events during development of nonpeptidergic DRG neurons. Neuron 54, 739–754 (2007).
Deppmann, C.D. et al. A model for neuronal competition during development. Science 320, 369–373 (2008).
Lonze, B.E., Riccio, A., Cohen, S. & Ginty, D.D. Apoptosis, axonal growth defects, and degeneration of peripheral neurons in mice lacking CREB. Neuron 34, 371–385 (2002).
Di-Poï, N., Montoya-Burgos, J.I. & Duboule, D. Atypical relaxation of structural constraints in Hox gene clusters of the green anole lizard. Genome Res. 19, 602–610 (2009).
Nakamura, H. & Funahashi, J. Introduction of DNA into chick embryos by in ovo electroporation. Methods 24, 43–48 (2001).
Zhuang, B., Su, Y.S. & Sockanathan, S. FARP1 promotes the dendritic growth of spinal motor neuron subtypes through transmembrane Semaphorin6A and PlexinA4 signaling. Neuron 61, 359–372 (2009).
Liu, Q. et al. Sensory neuron-specific GPCR Mrgprs are itch receptors mediating chloroquine-induced pruritus. Cell 139, 1353–1365 (2009).
Acknowledgements
We thank T. Sanger for green anole embryos, cDNA and assistance with staging, N. Marsh-Armstrong for frog embryos, F. Lefcort for antibodies, S. Sockanathan, B. Zhuang and C. Lee for reagents and technical assistance with chick electroporation, A. Kolodkin, M. Li, X. Dong and H. Song for helpful discussions and members of the Ginty laboratory for comments on the manuscript, discussions and assistance throughout the course of the project. This work was supported by US National Institutes of Health grant NS34814 (D.D.G.). M.R.C. and D.D.G. are investigators of the Howard Hughes Medical Institute.
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K.M. and D.D.G. initiated microarray screens for NGF-dependent genes. B.G.C. and M.R.C. generated the Hoxd1-null mice. T.G., K.M. and S.R.W. performed functional characterization of Hoxd1. T.G., K.M. and D.D.G. analyzed the data. T.G. and D.D.G. wrote the manuscript.
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Guo, T., Mandai, K., Condie, B. et al. An evolving NGF-Hoxd1 signaling pathway mediates development of divergent neural circuits in vertebrates. Nat Neurosci 14, 31–36 (2011). https://doi.org/10.1038/nn.2710
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DOI: https://doi.org/10.1038/nn.2710
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