The long term goal of this program is to determine how growth factor signaling pathways regulate early steps in the development of animal form. We focus on factors and signaling pathways that regulate formation on the nervous system. Projects address fundamental issues in signal transduction using well characterized vertebrate animal mode systems. Pone project has clinical overtones and represents the long term future of our program. Objectives and specific aims are as follows: PDGF and CNTF direct bipotent progenitor cells in the developing rat forebrain toward alternate fates-formation of neurons or formation of astrocytes. Dr. Stiles and colleagues will isolate CNTF and pDGF-inducible """"""""immediate early"""""""" genes that mediate these alternate fates. IGF 1 is an important survival factor for neurons in the rat hind brain. Cr. Greenberg will dissect a novel, PI3 kinase/Akt signaling pathway which is activated by IGF 1 to maintain survival. In both the central and peripheral nervous systems, TGFbeta family members direct the fate choice of multipotent neural progenitor cells. Dr. Whitman and this colleagues will examine the role of mammalian FAST-1 homologues in the regulation of TGFbeta- responsive promoters. PDGF regulates growth, survival and differentiation of glial cells, Dr. Roberts and his colleagues will define the molecular basis of synergy between PDGF and cAMP-PKA ectodermal tumors (PNETs) in children can be conceptualized as multipotent neural progenitor cells that are developmentally stalled. Drs. Pomeroy and Segal will define the role of the neurotrophin receptor Trk C as a prognostic indicator for medulloblastoma (a cerebellar PNET) and also identify genes that are coordinately controlled with TRK C in standard risk versus high risk medulloblastoma. The program faculty have a long and tangible history of productive interaction. They are drawn together by core facilities for phosphotyrosine-directed antibodies, adenovirus expression vectors, and Pediatric Neural Ectodermal Tumor Core.

National Institute of Health (NIH)
Eunice Kennedy Shriver National Institute of Child Health & Human Development (NICHD)
Research Program Projects (P01)
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Study Section
Pediatrics Subcommittee (CHHD)
Program Officer
Henken, Deborah B
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Dana-Farber Cancer Institute
United States
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Sauvageot, Claire; Dahia, Patricia L; Lipan, Ovidiu et al. (2005) Distinct temporal genetic signatures of neurogenic and gliogenic cues in cortical stem cell cultures. J Neurobiol 62:121-33
Ross, Sarah E; Greenberg, Michael E; Stiles, Charles D (2003) Basic helix-loop-helix factors in cortical development. Neuron 39:13-25
Oh, S Paul; Yeo, Chang-Yeol; Lee, Youngjae et al. (2002) Activin type IIA and IIB receptors mediate Gdf11 signaling in axial vertebral patterning. Genes Dev 16:2749-54
Brunet, Anne; Kanai, Fumihiko; Stehn, Justine et al. (2002) 14-3-3 transits to the nucleus and participates in dynamic nucleocytoplasmic transport. J Cell Biol 156:817-28
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Tran, Hien; Brunet, Anne; Grenier, Jill M et al. (2002) DNA repair pathway stimulated by the forkhead transcription factor FOXO3a through the Gadd45 protein. Science 296:530-4
Humbert, Sandrine; Bryson, Elzbieta A; Cordelieres, Fabrice P et al. (2002) The IGF-1/Akt pathway is neuroprotective in Huntington's disease and involves Huntingtin phosphorylation by Akt. Dev Cell 2:831-7
Whitman, M; Mercola, M (2001) TGF-beta superfamily signaling and left-right asymmetry. Sci STKE 2001:re1
Chan, J; Mably, J D; Serluca, F C et al. (2001) Morphogenesis of prechordal plate and notochord requires intact Eph/ephrin B signaling. Dev Biol 234:470-82

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