Functional Analysis of Drosophila NF1

Abstract : The protein that is defective in patients with neurofibromatosis type 1 (NF1) functions as a GTPase Activating Protein (GAP) for Ras, yet homozygous loss of a highly conserved Drosophila NF1 ortholog results in several phenotypes that are insensitive to manipulating Ras signal transduction, but rescued by increasing signaling through the cyclic AMP-dependent protein kinase A (cAMP/PkA) pathway. To study how NF1 modulates this pathway and to evaluate whether the cAMP/PKA pathway represents a valid therapeutic target in NF1,the aims of this project are to perform a comprehensive structure-function transgenic analysis to assess the in vivo importance of protein domains. We also aim to investigate whether different phenotypes reflect roles for NF1 as a GAP for either conventional Ras ortholog Ras1 or for R-Ras ortholog Ras2, to determine whether a neuroendocrine defect explains the non-autonomous NF1 growth deficiency, and to perform other experiments to determine why growth is restored by increasing PKA activity. Finally, with a long term goal of manipulating human NF1 expression levels, we aim to identify cis-acting elements and their cognate transcription factors that drive Drosophila NF1 expression in larval CNS neurons and in peripheral nerves.