Receptor Phosphatases and Process Outgrowth

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DESCRIPTION (provided by applicant): A key aspect of the development of many types of cells, particularly neurons, is that they must extend projections over long distances and varied terrains in order to interact with appropriate targets. In order to achieve this goal, projections carry on their surfaces molecules that allow them to detect and respond appropriately to external cues. The work proposed here seeks to understand how one particular kind of molecule, a receptor phosphatase we have identified and named HmLAR2, performs this function. Receptor phosphatases have been implicated, in systems from flies to rats, as key components of the signaling pathways that allow cells to respond in specific ways to environmental factors, both soluble and bound to other cells or extracellular matrices. We plan to examine how the dynamics of cell growth are affected when HmLAR2 is experimentally perturbed or deleted, or expressed ectopically in cells that normally do not express the corresponding gene. Having already identified a relevant external signal as well as a putative internal substrate that could mediate how this molecule affects cell growth, we now seek to understand further its mechanisms of action by using a preparation, the medicinal leech, that allows very refined live imaging of individual cells in the intact living embryo with sophisticated microscopes. In experiments up to this point we have learned that this molecule is critical for growth and the maintenance of migrating structures in one particular kind of cell that expresses it. We also seek to establish the generality of this observation by studying, in the same system, other cells that also express this molecule. Our long-term objective is to obtained detailed knowledge of the molecular pathways of which HmLAR2 is a member, to understand how this molecule is regulated by the cell, and to explain how, in molecular terms, it achieves its function as a transducer of external signals into internal responses. This detailed level of knowledge will then allow us to understand how pathological states that affect the function of this important class of surface receptor may lead to a breakdown in the development of tissues and organs, including nerve and muscle tissues, that is representative of some types human disease conditions.