The goal of this application is to understand the molecular signals that underlie the formation of cytoarchitecture in cerebellar development. Over the past few years, a number of studies have addressed cell adhesion/recognition molecules of the immunoglobulin gene superfamily (IgSF) in the nervous system. However, studies on the function of these molecules in neural development in vivo are sparse, and the understanding of their roles in establishing neuronal architecture remains largely elusive. The current application will address the role of the IgSF cell adhesion/recognition molecule contactin in cerebellar development using a combination of in vivo and in vitro approaches. Several lines of evidence indicate that contactin plays a pivotal role in regulating cellular interactions that control cerebellar development. This investigator has generated mice with disrupted contactin gene function which develop a severely ataxic phenotype with an onset of postnatal day 9. The mutation is lethal by postnatal day 18. Preliminary analyses of the mutant cerebellum have identified defects in granule neuron development. This neuron population, which, in the wild type, expresses contactin throughout postnatal cerebellar development, provides an opportune model to study the role of contactin in neural development. This project will focus on two major functions of contactin that are indicated from preliminary analyses of the knockout mice. First, using the knock-out mice, the investigator has obtained evidence for a role of contactin in regulating the number of granule cell precursors in the external germinal layer (EGL). The project will test several hypotheses, which will address if contactin-mediated cellular interactions are required for the proliferation, survival and/or maintenance of the undifferentiated state of granule neuron precursors in the EGL. Second, additional preliminary data have revealed a later role of contactin in the fasciculation of parallel fiber axons in the cerebellar molecular layer. The investigator proposes to investigate the mechanism by which contactin regulates this function, and will determine in vitro the ligands with which contactin interacts in controlling axon-axon interactions. These studies will move forward the understanding of the molecular basis of cerebellar development, and, in particular, provide an opportunity to dissect the function of an IgSF cell adhesion/recognition molecule in a biological setting. Thus, this work may set an example for future studies on a host of similar proteins.
