During embryogenesis, developing neurons project neurite processes that differentiate into an axon and dendrites in a highly specific manner, establishing the neural circuits critical to the function of the mature nervous system. The assembly and disassembly of actin filaments are crucial to axon initiation, growth and guidance. Proteins of the Actin Depolymerizing Factor/cofilin (AC) family bind to actin filaments (F-actin) and enhance their severing and depolymerization into actin monomers (G-actin). Extracellular signals affect neurite growth and guidance via alterations in actin reorganization through AC activity, and alterations in actin dynamics are central to axonogenesis of cultured hippocampal neurons. Thus, AC proteins, through their phosphorylation, may be the target of diverse signalling pathways controlling the differentiation of the axon. Studies in mammalian cells on the role and regulation of AC proteins have suffered from the need to overexpress mutant proteins to compensate for endogenous AC proteins. Here we propose to use neurons from ADF null mice and silence cofilin expression using siRNA. We will then rescue abnormal neuronal phenotypes with adenoviral-mediated expression of different AC mutants to determine the role of AC in axonogenesis and neurite outgrowth. ? ?
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