The discovery that the adult mammalian brain is capable of producing new neurons throughout the life of the animal provides the exciting possibility that we will 1 day be able to induce the production of neurons to replace those lost as a result of injury, disease or neurodegenerative disorders. To accomplish this, we will have to (1) understand how to induce resident neural stem cells to proliferate in order to provide neural progenitor cells, (2) learn how to bias the fate of these progenitor cells to the particular neural cell type(s) needed, and (3) direct the migration of these newborn cells to the locations where they are required. In this application, we propose to study the role of the receptor tyrosine kinase ErbB4 in the migration of cells that form the rostral migratory stream (RMS). In the adult rodent, neural progenitor cells born in the anterior region of the lateral ventricle migrate as chains of neurons in the RMS to the olfactory bulb where they differentiate into interneurons. We have shown that ErbB4 is expressed in these migrating progenitors and that neuregulin-1 (NRG1) is the most readily detected ErbB4 ligand expressed in the RMS. The preliminary analysis of mice that lack ErbB4 in neural tissue has revealed a disrupted RMS organization. We propose to first determine if these mice exhibit deficits in neural progenitor cell proliferation, survival, and differentiation. We will then determine if the loss of ErbB4 leads to a cell autonomous defect in migration. Next, we will evaluate the ability of the 3 distinct NRG1 types to influence progenitor migration both in vitro and in vivo. Lastly, we will investigate the possible role of integrins as modulators of ErbB4 signaling. Through these efforts, we hope to gain an improved understanding of the molecules that regulate neural progenitor cell proliferation, migration and differentiation.
