Zebrafish Model of NF1 for Structure-Function Analysis, Mechanisms of Glial Tumorigenesis, and Chemical Biology
Technical Report,01 May 2012,30 Apr 2015
Dana-Farber Cancer Institute Boston United States
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In collaboration with the Granato lab at Penn, the Epstein lab has discovered striking learning and memory defects in mutant fish. Our data provide compelling evidence that neurofibromin regulates learning and memory by distinct molecular pathways in vertebrates and that deficits produced by genetic loss of function are reversible. These findings support the investigation of cAMP signaling enhancers as a companion therapy to Ras inhibition in the treatment of cognitive dysfunction in NF1. In the Look lab, the zebrafish models of the NF1 tumor suppressor linked cancers of MPNST and glioma have been completely updated to make them optimal for the structure function studies. We established new transgenic lines with overexpression of the receptor tyrosine kinase PDGFRA, which accelerates disease onset and increases the penetrance of MPNST in nf1p53deficient zebrafish, to increase the precision of the structure function studies to elucidate the mechanism of tumor suppression by NF1. We also established a faithful model of high-risk neuroblastoma with loss of nf1 and successfully performed in vivo structure-function analysis of NF1. Our results demonstrated that the GAP activity of the GRD domain is required to mediate the tumor suppressor function of nf1 in MYCN-induced neuroblastoma tumorigenesis.