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Species-specific neuronal circuits directed by neurotrophic factor

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 > feathers.

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Species-specific neuronal circuits directed by neurotrophic factor

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  1. 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.

  2. Chick Mouse > hopping gait = sautiller > feathers > alternating locomotion > hairs, a cold adaptation necessary for the prevention of heat loss. Expect species specific differences in spinal circuitry

  3. Different innervation of skin in mammals and birds no nerve endings in the epidermis elaborate nerve endings in the epidermis

  4. 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)

  5. Somatosensory neurons are highly diverse Dorsal root ganglion (DRG) Spinal cord Proprioceptors TrkC/NT-3 Mechanoreceptors TrkB/BDNF Nociceptors Thermoceptors TrkA/NGF Ret/GDNF

  6. Neurotrophins and sensory neuron development > survival > maturation > axonal projections

  7. Summary Hypothesis Species are endowed with unique sensory capabilities encoded by divergent neural circuits. Onepotential 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-specificsignalingmodule induced by NGF and mediated by a rapidly evolving Hoxtranscription 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. The form of a scientific paper

  8. NGF and sensory neuron development Nociceptors - pain - temperature - touch - itch > survival > maturation > axonal projections

  9. Hox genes in development Hox genes pattern the rostro-caudal axis

  10. Hox genes pattern the rostro-caudal axis

  11. HoxD family – role in limb patterning (medio-lateral axis)

  12. 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 Chick DRG culture + NGF + NGF > differentially regulated genes detected by Q-PCR HoxD1

  13. Results 1. A screen for genes controlled by NGF signaling in mammalian nociceptors HoxD1 is an NGF regulated in mouse, but not in chick

  14. Fig. 1 HoxD1 expressed in mouse nociceptors, but not in chick

  15. 2. Developmental expression of Hoxd1 in different vertebrate species HoxD1 -/- WT Nociceptive innervation of the skin of Hoxd1−/− mice resembles that of non-mammalian vertebrates e.g. birds

  16. Fig. 2 Abnormal expression of Mrgbp4 in peptidergic neurons in HoxD1-/- mice

  17. 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

  18. Different patterns of nociceptor innervation of the spinal cord in mouse and chick

  19. 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.

  20. 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

  21. Electroporation of plasmid DNA into chick embryo neural tube

  22. 5. Ectopic Hoxd1 expression in chick nociceptors induces mammal-like traits > HoxD1 expression in chick suppressed deep layer nociceptor innervation in chick

  23. 6. Hoxd1−/− mice have deficits in cold sensitivity

  24. 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

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