Date of Award
Doctor of Philosophy (PhD)
Greg J. Bashaw
For the majority of axons, an essential step in proper guidance involves crossing the midline, and failure to do so often results in an inability to coordinate movement. Attraction to the midline depends in part on the highly conserved guidance receptor DCC, or Frazzled in Drosophila, which signals chemoattraction upon binding its ligand, Netrin. DCC mutations in humans are associated with mirror movement disorder, an inability to independently control the right and left sides of the body. Although Frazzled/Netrin signaling is required for many axons to cross the midline, netrin and frazzled/DCC mutants still exhibit significant midline crossing, implicating additional pro-crossing mechanisms. The Drosophila embryonic midline provides an ideal model to investigate nervous system development in vivo as it is genetically tractable and axon guidance cues are highly conserved. To identify additional pro-crossing pathways, we initiated a screen for modulators of midline crossing in a sensitized genetic background wherein Frazzled signaling is partially disrupted. Axon crossing defects in this background are enhanced by mutations in the transmembrane semaphorin, Sema-1a. Mutations in sema-1a also dominantly enhance crossing defects in a netrin mutant, indicating that Sema-1a functions in a Netrin independent pathway to promote midline crossing. Here we identify the transmembrane Semaphorin, Sema-1a, as a novel regulator of midline crossing in the Drosophila CNS. We show that Sema-1a functions as a receptor in response to the secreted Semaphorins, Sema-2a and Sema-2b, to promote midline crossing. In contrast to other examples of reverse signaling where Sema1a triggers repulsion through Plexin binding, in commissural neurons Sema-1a acts independently of Plexins to inhibit Rho and promote attraction to the midline. These findings suggest that Sema-1a reverse signaling can elicit distinct axonal responses depending on differential engagement of ligands and signaling effectors.
Hernandez-Fleming, Melissa C., "Sema-1a Reverse Signaling Promotes Midline Crossing In Response To Secreted Semaphorins" (2016). Publicly Accessible Penn Dissertations. 2334.