The long-term goals of this project are to identify factors that regulate dendritic differentiation in the developing central nervous system (CNS). These experiments are driven by the hypothesis that dendritic growth and differentiation in the cerebral cortex is regulated by developmentally and spatially restricted extracellular signals. To identify and characterize such signals we have developed primary cultures that allow the process of dendritic differentiation of cerebral cortex neurons to be studied in vitro. These experiments will allow me to initiate a more comprehensive search for novel differentiation regulatory genes using an expressing cloning strategy.
The specific aims of this project are: 1. To identify signals that regulates the patterning of apical dendrites during cortical development. The focus of these experiments is to determine whether membrane-bound or diffusible factors regulate the oriented outgrowth of apical dendrites toward the pial surface. We will also characterize the spatial and temporal distribution of these signals during cortical development, and will examine their chemorepulsive or chemoattractive nature. 2. To identify signals that regulate lamina-specific branching and remodeling of cortical dendrites. In these experiments we will characterize cortex-derived signals that regulate dendrite outgrowth and branching. We will also address whether signals that regulate dendritic differentiation are present in a layer-specific or temporally regulated manner in the developing cortex. These studies will contribute to our understanding of the molecular mechanisms in the regulation of neuronal differentiation. The increasing complexity of growth control pathways that regulate neuronal differentiation has been paralleled by the identification of proteins that regulate normal development. The identification of additional molecules that induce neuronal differentiation and survival should lead to significant advances in our understanding of the mechanisms involved in regulating neuronal differentiation, and yield more general insights into the mechanisms by which perturbation of growth-promoting signals may lead to disease.
