The complex pattern of neuronal circuitry is established during embryonic development as neurons extend axons that navigate with temporal an spatial precision to their synaptic targets. The selection of specific axon pathways and innervation of synaptic target sites is controlled by molecules located in the environment of the tips of the growing axons. The recognition of these guidance cues is thought to be mediated by receptors on the growth cone surface which, upon activation, rearrange the neuronal cytoskeleton and control the extension and orientation of growing axons. The purpose of this program project is to elucidate cellular and molecular mechanisms that lead to the establishment of functional axon connections in the developing vertebrate nervous system. The participating laboratories each study cell surface or extracellular matrix molecules that are either known or promising candidates for the involvement in axon recognition and guidance. The specific molecules that are the subject of this program project are the immunoglobulin-like cell adhesion molecule NILE L1 (project I), the GPI-linked cadherin cell adhesion molecule T-cadherin (project II), the Eph-related receptor-type tyrosine kinase Cek8 (Project III) and the secreted chrondroitin sulfate proteoglycan Brevican (Project IV). All of these molecules are expressed in the developing nervous system. Because they contain structural cell adhesion motifs, such as immunoglobulin-like domains (NILE/L1, Cek8, Brevican), fibronectin-type III repeats (NILE/L1, Cek8), a lectin-like domain closely related to selectins (Brevican) or cadherin structural repeats (T-cadherin), these molecules are all postulated to be involved in cell recognition events during neural development. The goal of this program is to determine the cellular and molecular interactions in developing neural tissues in which these molecules play a role. The functions of NILE/L1, T-cadherin, Cek8 and Brevican in neurite growth will be explored in vitro. The Program Project Core consists of a facility that will assist all participating laboratories with 1) a standardized service to establish primary neural cultures for the analysis of neurite growth and growth cone behavior and 2) computerized data collection and analysis of such cultures. This core component will be an extension of the Cell Behavior Analysis Core B of the current Program Project. The Program Project will provide an intellectually stimulating and interactive environment in which the molecular nature underlying the establishment of the complex neuronal circuitrary is the common and uniting theme.
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