description): The principal investigator has created a transgenic mouse model for caudal regression, a birth defect associated with diabetic pregnancies and characterized by growth abnormalities in the caudal region of the embryo. Using this model for gene discovery, he has identified the mouse gene Punc. Punc encodes a novel cell adhesion molecule of the immunoglobulin superfamily with particular resemblance to the axonal guidance receptor encoded by the gene Deleted in Colorectal Cancer, a tumor suppressor gene. The expression of Punc is correlated with proliferating cells of the early nervous system and lateral plate mesoderm and ceases when those cells begin to differentiate. Chromosomal mapping placed the human PUNC gene near a genetic locus that is linked to Bardet-Biedl Syndrome. Besides mental retardation, retinopathy, renal failure, obesity and diabetes, this disorder includes poly-, syn- and brachydactyly as well as hypogonadism, presumably due to developmental perturbations that affect cell proliferation. The expression of Punc in the mouse embryo is consistent with phenotypes of Bardet-Biedl Syndrome, and Punc mutant mice display hypogonadism. These results prompted the hypothesis that the Punc gene plays a central role for proliferative processes, and that disturbing Punc gene function would lead to growth abnormalities such as those observed in caudal regression or Bardet-Biedl syndrome. To elucidate the biological function of the Punc gene and define its role for birth defects, the investigator proposes to pursue the following specific aims: (1) to investigate the role of Punc as a cell adhesion molecule; (2) to investigate whether Punc-mediated adhesion is a signal for control of cell proliferation or prevention of cell death in the embryo; and (3) to map functional motifs of the cytoplasmic domain of Punc for transduction of the adhesion signal. Together, these studies will define cellular and developmental functions of Punc and provide mechanistic insight how perturbations of cell proliferation in the embryo can lead to morphogenetic birth defects.
