Mummy regulates slit-robo signaling to mediate axon guidance in drosophila embryonic nerve cord

Abstract

During human brain development, precise connections have to be established to maintain the structural and functional integrity of the nervous system. Mutations in axon guidance molecules have been reported to cause various human nervous system disorders. The Slit-Robo signaling pathway is a well-studied evolutionarily conserved axon guidance mechanism. Slit is a chemo-repellant secreted by midline glial cells and binds to specific receptor Roundabout to mediate axonal repulsion. However, molecules involved in finer regulation of this pathway are unknown. I used the Drosophila embryonic nervous system as an experimental model to study the axon guidance mechanism during nervous system development. Previous work from the lab has demonstrated the transport of Slit from the midline to the longitudinal axon tracts. A Slit transport mutant allele mmyslm was discovered, revealing a novel role for the Mummy protein in regulating Slit-Robo signaling pathway during development. Mummy regulates Slit post-translationally during nerve cord development. Lack of functional Mummy significantly reduces the transport of Slit from the midline to the longitudinal tracts and exhibits axon guidance defects. In mmyslm, the longitudinal axon tracts are closer to the midline and are not discrete suggesting that the lateral specification of the longitudinal tracts is affected. The guidance defects only manifest later in development since early patterning of the nerve cord is regulated by maternally deposited mmy mRNA. This signifies the importance of Mummy protein since a continuous supply of functional Mummy is required for proper patterning of the nerve cord. Mummy also regulates glycosylation of the Slit protein. We have demonstrated that glycosylation of Slit is not essential for binding to its receptor Roundabout. Glycosylation seems to play an important role in regulating the cleavage of Slit protein. Mummy also regulates the Slit specific Robo receptor protein levels post-translationally. Absence of Mummy leads to significant down-regulation of Robo and Robo3 receptor proteins. Transport of Slit is independent of Robo-receptor protein suggesting that Slit may bind to a transporter molecule and transport it to the axon tracts. This study emphasizes the importance of Mummy in regulating the Slit-Robo signaling pathway to generate a functional nervous system during development.

Description
Keywords
Axon guidance, Slit, Roundabout, Neuronal Development, axonal repulsion
Citation