The Role of ERM Proteins in Axonal Development

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DESCRIPTION (provided by applicant): Ezrin, radixin, and moesin, collectively known as the ERM proteins, serve as linkers between the membrane associated molecules and the underlying cytoskeleton. Recently, a binding interaction between the ERM protein, ezrin, and the developmentally important adhesion molecule, L1, has been discovered. Furthermore, disruption of ERM protein function has been shown to affect axonal outgrowth in cell culture models. Because the substrate for adhesion molecules cannot be recapitulated in vitro, it is not currently possible to fully explore the putative role of ERM proteins, via their simultaneous interactions with adhesion molecules and the cytoskeleton, in axonal development. In Aim 1 of this proposal the plausibility of an interaction between adhesion molecules and ERMs, which is relevant to axonal sprouting in the developing cerebral cortex, will be tested with immunohistochemistry and Western blotting. In Aim 2, an ERM dominant negative, a constitutively active ERM, and controls will be expressed in neurons whose axons project into the intermediate zone of the cerebral cortex via in utero gene transfer. Comparative microscopic analysis of axonal development markers and morphology in animals expressing loss of function, gain of function, and control constructs will elucidate ERM function in axon outgrowth. A complete understanding of ERM function will contribute not only to developmental neurobiology, but also to the body of knowledge that will likely be needed if axonal regeneration by recapitulation of development is to be undertaken for therapeutic reasons in diseases such as stroke, Alzheimer's disease and spinal cord injury.