Functional analysis of semaphorin-1a in the developing PNS

During development, elongating axons must make important steering decisions in order to establish the intricate and precise web of connections in a functional nervous system. Developing axons are currently believed to be guided by cues present in their local environment which act through four general mechanisms: chemoattraction/chemorepulsion (secreted molecules), and contact mediated attraction/contact mediated repulsion (cell surface molecules) which effectively steer the axon growth cone along a directed path to its correct target. The semaphorin family of secreted and cell surface glycoproteins were first described in 1993 and are thought to play an integral role in axon pathfinding by acting as chemorepulsive guidance molecules. However, although chemorepulsion had been demonstrated for several secreted semaphorin family members, little was known about the function of the majority of the semaphorin members, including the transmembrane forms, at the time that this thesis project began in 1995. The aim of this thesis was to investigate the role of Semaphorin-1a, the founding member of the semaphorin family, using the highly accessible peripheral nervous system of the developing grasshopper limb bud with the aspiration of obtaining a better understanding of the functional role of a transmembrane semaphorin. The studies outlined in this thesis investigate the effects of Sema-1a on the pathfinding events of several early arising neurons. The data presented herein describe the first evidence of an attractive guidance activity for a semaphorin family member and highlights the complexity and utility of the semaphorins in axon guidance.Medicine, Faculty ofGraduat