Laboratory for Neuronal Differentiation and Regeneration

We are interested in the physiological roles of a newly identified family of neurotrophic factors, the GDNF Family Ligands (GFLs). The GFLs signals through a multicomponent receptor complex consisting of the RET receptor tyrosine kinase and a GPI-anchored cell surface protein, GFRα. We have taken mouse genetic approaches to understand how the GFLs and their receptors regulate neural development. These studies have revealed that GFL signaling plays a critical role for the development of enteric, sensory and autonomic nervous systems, establishing the GFLs as neurotrophic factor family of equal importance to the better-known neurotrophins. As GFL signaling is particularly required for axon growth, axon guidance and neuronal migration during development of various neuronal populations, we focus our efforts on elucidating the molecular mechanisms by which the GFLs regulates cytoskeletal reorganization. We are also conducting systematic gene expression analysis of developing enteric and autonomic neurons to achieve a better understanding of the molecular mechanisms regulating development and maturation of these neurons. Our ultimate goal is to contribute to the development of stem cell-based therapies for diseases in the nervous system by gaining insight into the roles played by specific neurotrophic factor signaling pathways.

Research Subjects

• Elucidation of the physiological function of GFLs in development, maturation and regeneration of the nervous system
• Understanding the biological signficance of the intracellular signal transduction pathways activated by the RET/GFRα receptor complex
• Elucidation of the mechanisms underlying RET-activated cell migration and neurite outgrowth
• Elucidation of the molecular mechanisms underlying the pathogenesis of neurocristopathies caused by RET mutations

Publications

1. Nagashimada, M., Ohta, H., Li, C., Nakao, K., Uesaka, T., BrunetJ-F., Amiel, J., Trochet, D., Wakayama, T., and Enomoto, H.:
   "Autonomic neurocristopathy-associated mutations in PHOX2B dysregulate Sox10 expression."
   Journal of Clinical Investigation, 122, 3145-3158. (2012)
2. Nishiyama, C., Uesaka, T., Manabe, T., Yonekura, Y., Nagasawa, T., Newgreen, DF., Young, HM., and Enomoto, H.:
   "Trans-mesenteric neural crest cells are the principal source for the colonic enteric nervous system."
   Nature Neuroscience, 15, 1211-1218. (2012)
3. Uesaka T. and Enomoto, H.:
   Neural precursor death is central to the pathogenesis of intestinal aganglionosis in Ret hypomorphic mice."
   Journal of Neuroscience, 30, 5211-5218. (2010).
4. Enomoto, H.:
   "Death comes early: apoptosis observed in ENS precursors."
   Neurogastroenterology & Motility, 21, 684-687 (2009)
5. Uesaka, T., Nagashimada, M., Yonemura, S., and Enomoto, H.:
   "Diminished Ret expression compromises neuronal survival in the colon and causes intestinal aganglionosis in mice."
   Journal of Clinical Investigation, 118, 1890-1898 (2008)
6. Gould, T. W., Yonemura, S., Oppenheim, R. W., Ohmori, S., and Enomoto, H.:
   "The neurotrophic effects of glial cell line-derived neurotrophic factor on spinal motoneurons are restricted to fusimotor subtypes."
   Journal of Neuroscience, 28, 2131-2146 (2008)
7. Uesaka, T., Jain, S., Yonemura, S., Uchiyama, Y., Milbrandt, J., and Enomoto, H.:
   "Conditional ablation of GFRα1 in postmigratory enteric neurons triggers unconventional neuronal death in the colon and causes a Hirschsprung's disease phenotype."
   Development, 134, 2171-2181 (2007)
8. Enomoto, H., Hughes, I., Golden, J., Baloh, R.H., Yonemura, S., Heuckeroth, R.O., Johnson, E.M.Jr., and Milbrandt, J.:
   "GFRα1 expression in cells lacking RET is dispensable for organogenesis and nerve regeneration"
   Neuron, 44, 623-36 (2004)
9. Enomoto, H., Crawford, P.A., Gorodinsky, A., Heuckeroth, R.O., Johnson, E.M.Jr., and Milbrandt, J.:
   "RET signaling is essential for migration, axonal growth and axon guidance of developing sympathetic neurons"
   Development, 128, 3963- 3974 (2001)
10. Enomoto, H., Heuckeroth, R.O., Golden, J.P., Johnson, E.M.Jr., and Milbrandt, J.:
    "Development of cranial parasympathetic ganglia requires sequential actions of GDNF and neurturin"
    Development, 127, 4877-4889 (2000)