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Species-specific neuronal circuits directed by neurotrophic factor control of transcriptional programmes > novel neural circuits arise during evolution to encode unique behaviors among different animal species. Chick Mouse > hopping gait = sautiller > alternating locomotion > feathers > hairs, a cold adaptation necessary for the prevention of heat loss. Expect species specific differences in spinal circuitry Different innervation of skin in mammals and birds elaborate nerve endings in the epidermis no nerve endings in the epidermis Diversité des neurones sensoriels périphériques des ganglions rachidiens Ganglion Rachidien Dorsaux (DRG) TrkA ou c-Ret TrkC TrkB et/ou c-Ret Moelle épinière Neurones prorioceptifs Neurones mécanoceptifs Neurones nociceptifs Marmigère and Ernfors Nature Reviews Neuroscience 8, 114–127 (February 2007) Somatosensory neurons are highly diverse Spinal cord Dorsal root ganglion (DRG) Proprioceptors Mechanoreceptors TrkC/NT-3 TrkB/BDNF Nociceptors Thermoceptors TrkA/NGF Ret/GDNF Neurotrophins and sensory neuron development > survival > maturation > axonal projections Summary The form of a scientific paper Hypothesis Species are endowed with unique sensory capabilities 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 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. Results We identified a species-specific signaling module induced by NGF and mediated by a rapidly evolving Hox transcription factor, Hoxd1. Mice lacking Hoxd1 display altered nociceptor circuitry which resembles that normally found in chicks. Conversely, ectopic expression of Hoxd1 in developing chick nociceptors promotes a pattern of axonal projections reminiscent of the mouse. Conclusion We propose that conserved growth factors control divergent neuronal transcriptional events which mediate interspecies differences in neural circuits and the behaviors they control. NGF and sensory neuron development Nociceptors - pain - temperature - touch - itch > survival > maturation > axonal projections Hox genes in development Hox genes pattern the rostro-caudal axis Hox genes pattern the rostro-caudal axis HoxD family – role in limb patterning (medio-lateral axis) 1. Search for transcriptional targets of NGF different between birds and mammals i. Genes enriched in nociceptors ii. NGF-regulated genes expressed in nociceptors in vivo iii. mouse DRG explants grown in the presence or absence of NGF for identification of NGF-dependent genes expressed in nociceptors in vitro. > NGF dependent genes in mouse nociceptors Mouse DRG culture + NGF Chick DRG culture + NGF > differentially regulated genes detected by Q-PCR HoxD1 Results 1. A screen for genes controlled by NGF signaling in mammalian nociceptors HoxD1 is an NGF regulated in mouse, but not in chick Fig. 1 HoxD1 expressed in mouse nociceptors, but not in chick 2. Developmental expression of Hoxd1 in different vertebrate species WT HoxD1 -/- Nociceptive innervation of the skin of Hoxd1−/− mice resembles that of non-mammalian vertebrates e.g. birds Fig. 2 Abnormal expression of Mrgbp4 in peptidergic neurons in HoxD1-/- mice 3. Hoxd1 instructs nociceptor central axonal projections within the mammalian spinal cord Mirroring species-specific differences in innervation of the skin, the patterns of nociceptive axonal projections within the spinal cords of mammals and birds are also distinct > ectopic innervation of deep layers of the spinal cord Different patterns of nociceptor innervation of the spinal cord in mouse and chick 4. Hoxd1 instructs nociceptor central axonal projections within the mammalian spinal cord - suggests that Hoxd1 mediates NGF-dependent suppression of nociceptor projections into deep layers of the spinal cord. In Mouse Loss of NGF or Loss of HoxD1 > chick-type spinal cord innervation What is effect of expressing HoxD1 in chick DRG neurons? The gain-of-function experiment Electroporation of plasmid DNA into chick embryo neural tube 5. Ectopic Hoxd1 expression in chick nociceptors induces mammal-like traits > HoxD1 expression in chick suppressed deep layer nociceptor innervation in chick 6. Hoxd1−/− mice have deficits in cold sensitivity Conclusion > Hoxd1 instructs development of mammal-specific features of nociceptive neural circuitry. > behavioral sensitivity to extreme cold is markedly compromised in Hoxd1 mutant mice > suggests HoxD1 was co-opted by nociceptors in mammals for cold sensation