Function of polysialic acid-NCAM in tectal development

Sloan-Kettering Institute For Cancer Res, New York NY

Investigators

Abstract

DESCRIPTION (provided by applicant): The broad long-term objective of this research proposal is to gain insight into the role of cell-cell and cell-matrix interactions during the development of neural networks in the vertebrate CNS. The model system used for the proposed studies is the chick visual system, a favorable model for studies of neuronal specificity because it shares many features of the mammalian cortex but is more accessible to experimental manipulation. The primary objective is to test the hypothesis that polysialylated-NCAM, which can promote changes in tissue structure by modulating cell-cell interactions, plays an important role during the topographical targeting of retinal ganglion cell (RGC) axons and the development of stereotyped lamina-specific connections between RGC and tectal dendrites. The specific aims of the research proposal utilize PSA loss-of-function studies to remove PSA prior to the development of tectal laminae and RGC innervation of the tectum, and PSA gain-of-function studies to misexpress PSA in inappropriate regions of the tectum and beyond the period when it is normally down-regulated. Retroviral-mediated expression of the two enzymes responsible for NCAM polysialylation, PST and STX, will be used to mediate ectopic expression of PSA-NCAM. Taken together, these perturbations in PSA expression are aimed at demonstrating that PSA is not only necessary but also sufficient to induce plastic behaviors during axonal and dendritic targeting in the developing visual pathway. Implications of this research include a better understanding of the role of PSA in aging and in neurological disorders such as schizophrenia which are associated with decreased PSA expression and alterations in synaptic plasticity.