Laboratory for Neuronal Differentiation and Regeneration
Research Areas
| 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. |  Team Leader Hideki ENOMOTO (M.D., Ph.D.)  |
Research Subjects
| (1) | Elucidation of the physiological function of GFLs in development, maturation and regeneration of the nervous system |
| (2) | Understanding the biological signficance of the intracellular signal transduction pathways activated by the RET/GFRα receptor complex |
| (3) | Elucidation of the mechanisms underlying RET-activated cell migration and neurite outgrowth |
| (4) | Elucidation of the molecular mechanisms underlying the pathogenesis of neurocristopathies caused by RET mutations |
List of Selected Publications
| (1) | Gould, T.W. and Enomoto, H.: "Neurotrophic modulation of motor neuron development." The Neuroscientist, 15, 105-116 (2009). |
| (2) | Callahan, T., Young, H.M., Anderson, R.B., Enomoto, H., and Anderson, C.R.: "Development of satellite glia in mouse sympathetic ganglia: GDNF and GFRa1 are not essential." Glia, 56, 1428-1437 (2008). |
| (3) | 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). |
| (4) | 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). |
| (5) | 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). |
| (6) | Vohra, B.P.S., Tsuji, K., Nagashimada, M., Uesaka, T., Wind, D., Fu, M., Armon., J., Enomoto, H., and Heuckeroth, R.O.: "Differential gene expression and functional analysis implicate novel mechanisms in enteric nervous system precursor migration and neuritogenesis." Developmental Biology, 298, 259-271 (2006). |
| (7) | 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). |
| (8) | Crowder, R.J., Enomoto, H., Yang, M., Johnson, E.M. Jr., and Milbrandt, J.: "Dok-6, a novel p62 Dok family member, promotes Ret-mediated neurite outgrowth." Journal of Biological Chemistry, 279, 42072-42081 (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). |