The cadherins are a family of cell surface proteins that mediate adhesion between embryonic cells. Cadherins are expressed throughout neural development and have been proposed to play important roles in establishing domains of selective adhesion that serve to regionalize the neural tissue and form specific neural circuits. Recently a new family if cadherin like genes, the protocadherins can function as cell adhesion molecules, and many are expressed in the adult nervous system. Thus, an important question is whether protocadherins function to mediate ell adhesion in the developing vertebrate nervous system. Thus, an important question is whether protocadherins function to mediate cell adhesion in the developing vertebrate nervous system, establishing regions of differential cell adhesion that serve to regionalize neural tissue. This study proposes an in depth analysis of one such protocadherin NF- protocadherin (NFPC), isolated from mouse embryos. NFPC is expressed in a restricted group of cells in the embryonic mouse nervous system, including a sub-population of motor neurons. Experiments proposed in this grant will dissect the role of NFPC in mediating cell adhesion during differentiation of motor neurons in the embryonic mouse spinal cord. Accordingly, this grant proposes to first identify the neural subtypes that express NFPC. The function of NFPC in these cells will then be examined by ectopic expression of wildtype and dominant-negative NFPC constructs in the embryonic mouse neural tube. Finally, a mouse with a targeted deletion of NFPC will be generated and analyzed for defects in motor neuron segregation and axonal outgrowth. These studies will provide insights into the molecular mechanisms by which the vertebrate nervous system forms, as well as an elucidation of how- protocadherin contributes to this process. Thus, these studies will lead to a better understanding of how alterations in cell adhesion can contribute to the etiology of neural defects and cancer.
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