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An evolving NGF-Hoxd1 signaling pathway mediates development of divergent neural circuits in vertebrates

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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Figure 1: NGF signaling induces Hoxd1 expression in mammalian, but not avian, embryonic nociceptors.
Figure 2: Hoxd1 instructs development of mammal-specific features of nociceptor axonal connections in the skin.
Figure 3: Hoxd1 controls a species-specific pattern of nociceptor axonal connectivity in the spinal cord.
Figure 4: NGF signaling modulates central axonal projections of mammalian nociceptors in the spinal cord.
Figure 5: Ectopic expression of Hoxd1 in chick nociceptors impairs their axonal ingrowth into the lateral spinal cord.
Figure 6: Behavioral responses of Hoxd1−/− mice to somatosensory stimuli.

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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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Correspondence to David D Ginty.

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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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