JHIBRG:Abstract May 17 2007

In early embryonic development, signaling is important for motor axon growth cones to properly innervate their muscle targets. Attractive and repulsive guidance cues are required for the establishment of these stereotypic trajectories. One family of signaling molecules, the Semaphorins, comprises a large family of conserved secreted and membrane bound proteins. Semaphorin receptors, Plexin proteins, function as entry points for downstream signaling events critical for correct growth cone guidance. MICAL, a large cytosolic protein that interacts with Drosophila PlexA, was identified as a novel intracellular mediator of repulsive semaphorin signaling resulting from the transmembrane guidance cue Sema-1a. MICALs are conserved from fruit flies to mammals and are large, multidomain, cytosolic proteins. They are expressed in both neuronal and nonneuronal tissues from embryonic development to adulthood. Furthermore, MICAL is expressed in the CNS axons and motor neurons of the Drosophila embryo. Previous studies indicate that MICAL loss-of-function (LOF) and gain-of-function (GOF) abolish proper ISNb and SNa pathway motor axon pathfinding in Drosophila embryos. However one copy of a MICAL transgenic construct restored MICAL function in a homozygous MICAL null mutant background. From sequence analysis, MICAL is comprised of N-terminal Flavoprotein Monooxygenase domain(FM) that may provide a critical role in signaling for axon guidance. Here I show that the transgenic lines of FM domain alone showed gross developmental defects. There has been reports regarding a downstream molecule CRMP that it is involved in the Semaphorin-Plexin signaling pathway. However whether it serves as a axon guidance molecule in the context of Semaphorin mediated signalling pathway in vivo has not been clear. Also whether it may interact with MICAL and serve as a substrate has not been shown yet. Here we show some preliminary evidence that CRMP may be involved in axon guidance in vivo and genetically interact with the Semaphorin signaling pathway.

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