JHIBRG:Abstract Apr 3 2008

A Small GTPase invloved in Semaphorin downstream signaling

The establishment of complex and precise neuronal connections during development is a major puzzle. Neuronal connections are in part formed by the highly motile structure at the axon’s growing tip that senses guidance cues and then instructs the axon which way to grow (Tessier-Lavigne and Goodman, 1996). This process is highly dependent upon the nature of the extracellular ligand-receptor signaling mechanism that is transduced into intracellular signaling cascades essential for axonal steering (Tran et al. 2007). Semaphorins are a family of both secreted and transmembrane ligands that act as either attractive or repulsive axon guidance cues (Pasterkamp and Kolodkin, 2003). Plexins are phylogenetically conserved proteins that serve as the major receptors for both secreted and transmembrane semaphorins (Tamagnone et al. 2000). Plexins are known to interact with a variety of distinct intracellular signaling proteins in order to transduce guidance information; however at present our knowledge of these intracellular signaling pathways and how they function in vivo is still incomplete (Tran et al. 2007)). Previously an enhancer/suppressor genetic screen designed to identify semaphorin pathway signaling components was performed . As a consequence, Rap1, a GTPase that regulates among other pathways integrin signaling (Kooistra et al. 2007), was isolated as a suppressor of a heterologous Sema-1a gain-of-function (GOF) phenotype in the CNS. Interestingly, rap1 mutants show motor axon guidance phenotypes similar to Sema-1a and PlexA mutants and also genetically interact with Sema-1a mutants. Further elucidating the role of Rap1 in the context of Sema-1a mediated motor axon guidance in Drosophila and similarly in the mammalian system will be the goal.