This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. The subproject and investigator (PI) may have received primary funding from another NIH source, and thus could be represented in other CRISP entries. The institution listed is for the Center, which is not necessarily the institution for the investigator. The cadherins are a family of cell surface proteins that mediate adhesion between embryonic cells. Cadherins are expressed throughout neural development and are proposed to play important roles in establishing domains of selective adhesion that serve to regionalize the neural tissue and form specific neural circuits. Protocadherins are a newly identified subfamily of the cadherins, but whose functions in neural development are unknown. At least some protocadherins can function as cell adhesion molecules, and many are expressed in the 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. Our research involves an in depth analysis of one such protocadherin, chicken protocadherin 1 (cPcdh1), in the developing vertebrate nervous system. In the chick embryo, cPcdh1 is expressed in the embryonic nervous system, where it is restricted to developing motor neurons in the CNS and to coalescing neural crest cells in the dorsal root ganglia (DRG). This expression pattern suggests that cPcdh1 plays important roles in cell adhesion in the formation of the peripheral nervous system in vertebrates. To investigate the role of cPcdh1 in the embryonic chick nervous system, we have ectopically expressed, via in ovo electroporation, both wildtype and dominant-negative cPcdh1 constructs in the chick neural tube and neural crest. Ectopically expressing embryos are then examined for the proper migration of the neural crest cells and their subsequent coalescing to form the DRG. Current results suggest that expression of a dominant-negative cPcdh1 construct leads to abnormal neural crest migration in which neural crest cells fail to cease migration in the DRG and instead migrate to more ventral regions in the embryo, particularly the sympathetic ganglia. In contrast, ectopic expression of a full-length cPcdh1 construct results in a majority of neural crest cells ceasing migration in the DRG. In comparison, when a different cell adhesion molecule, N-cadherin, is disrupted, the neural crest cells also migrate past the DRG, but now preferentially migrate to the ventral branch and become Schwann cells. We are currently confirming these results using small inhibitory RNA (siRNA) to disrupt cPcedh1 or N-cadherin expression in neural crest cells. This research is being conducted by a graduate student in the lab, Judy Bononi, and our preliminary results formed the basis for a NSF proposal that was submitted in January 2006.
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