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 one day be able to induce the production of neurons to replace those lost as result of injury, disease or neurodegenerative disorders. In order 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 one subfamily of protein-tyrosine kinase receptors, the ErbBs, and their ligands, the neuregulins (NRGs), in the neurogenesis and migration of cells that form the rostral migratory stream (RMS). In the adult rat, neural progenitor cells born in the anterior region of the lateral ventricle migrate as chains of neurons in the RMS to how the olfactory bulb where they differentiate into interneurons. We have shown that 3 of the 4 ErbB receptors are expressed in the RMS and that all 3 NRGs are expressed in the olfactory bulb and in and in the regions of the cortex adjacent to the stream. In vitro, NRG-1 appears to block the formation of chains of migrating neurons and to disperse chains that have already formed. We propose to first characterize the sites of expression of the ErbB genes and the NRGs in the RMS of early postnatal and adult rats, identify the cell types in the RMS that express these genes, determine whether added recombinant NRG protein influences the proliferation rate of neural progenitors rate of neural progenitors cell proliferation, migration and differentiation.
|Koyama, Sachiko; Soini, Helena A; Foley, John et al. (2014) Pheromone-induced cell proliferation in the murine subventricular zone. Biochem Soc Trans 42:882-5|
|Seshadri, Saurav; Kamiya, Atsushi; Yokota, Yukako et al. (2010) Disrupted-in-Schizophrenia-1 expression is regulated by beta-site amyloid precursor protein cleaving enzyme-1-neuregulin cascade. Proc Natl Acad Sci U S A 107:5622-7|
|Ghashghaei, H T; Weber, Janet; Pevny, Larysa et al. (2006) The role of neuregulin-ErbB4 interactions on the proliferation and organization of cells in the subventricular zone. Proc Natl Acad Sci U S A 103:1930-5|
|Anton, E S; Ghashghaei, H T; Weber, Janet L et al. (2004) Receptor tyrosine kinase ErbB4 modulates neuroblast migration and placement in the adult forebrain. Nat Neurosci 7:1319-28|
|Yau, Hau-Jie; Wang, Hsiao-Fang; Lai, Cary et al. (2003) Neural development of the neuregulin receptor ErbB4 in the cerebral cortex and the hippocampus: preferential expression by interneurons tangentially migrating from the ganglionic eminences. Cereb Cortex 13:252-64|