Neural cell adhesion molecules are likely to play a critical role in cell migration, axon outgrowth and synaptogenesis during the development of the central nervous system (CNS). Although a variety of cell adhesion molecules that promote or inhibit neurite extension have been identified, little is known about the cell recognition events that lead to synaptogenesis. This proposal focuses on a recently identified cell adhesion molecule, P84, that is expressed in many sites of postnatal synaptogenesis in the CNS. The P84 antigen, a 85 kD glycoprotein, has been purified and the amino terminal sequence has been determined. P84 coated growth substrates promote neuronal attachment and neurite outgrowth that is distinct from the pattern observed with other cell adhesion molecules, such as L1 or NCAM. Cerebellar granule cells growing on P84-coated substrates extend neurites with large growth cones and very active filopodia. cerebellar granule cells express P84, but only after 3-4 days in culture, after cell-cell contacts have occurred. Some cells which do not express P84, including astrocytes and the hypothalamic-derived GT1-7 cell line, attach to P84 indicating that P84 must bind to a heterophilic receptor. In this proposal three aims will be pursued: First, P84 cDNA will be isolated to allow comparison of the P84 sequence to that of other known cell adhesion molecules and to provide the molecular reagents to analyze P84 expression in vivo and to alter the expression in vitro. Second the heterophilic receptor for P84 will be identified and cloned. Receptor identification will be important for understanding the regulation of P84 mediated interactions. Finally, cell culture experiments are proposed to examine the role of P84 in axon guidance and synaptogenesis in the cerebellum, a region of the CNS that strongly expresses P84. Ultrastructural studies will help to pinpoint the time of expression of P84 in the developing cerebellum and will allow the applicant to determine which types of cell-cell interactions are associated with P84's appearance. These studies will help elucidate mechanism of axon growth and synapse formation which are fundamental processes in human brain development and which are likely to play important roles in recovery from stroke and other traumatic injury to the brain. (paraphrased from application).
| Comu, S; Weng, W; Olinsky, S et al. (1997) The murine P84 neural adhesion molecule is SHPS-1, a member of the phosphatase-binding protein family. J Neurosci 17:8702-10 |
| Eckert, C; Olinsky, S; Cummins, J et al. (1997) Mapping of the human P84 gene to the subtelomeric region of chromosome 20p. Somat Cell Mol Genet 23:297-301 |
