FEEDBACK REGULATION OF NEUROGENESIS IN MAMMALS

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DESCRIPTION (Investigator's Abstract): The complexity of structure and function of the mammalian nervous system is dependent on the generation, during development, of a large and complex assortment of neurons: this process is known as neurogenesis. It has been known for many years that neurogenesis in the embryonic nervous system gradually slows as development proceeds, eventually halting as neuronal progenitors give rise to terminally differentiated neurons, but the molecular basis of this phenomenon is unknown. However, recent studies in this laboratory, using the mouse olfactory epithelium (OE) model system, have provided a clue concerning the basis of this phenomenon: these studies indicate that differentiated olfactory receptor neurons (ORNs) produce a signal that feeds back to inhibit neurogenesis by their own progenitor cells. Preliminary experiments indicate that Bone Morphogenetic Protein 4 (BMP4), a member of the TGFbeta superfamily of polypeptide growth factors, mimics this growth inhibitory signal, and that BMP4 is highly expressed in OE. These data suggest that BMP4 may be a crucial negative regulator of neurogenesis in the OE, and perhaps in other areas of the nervous system as well. To characterize the cellular basis of BMP4s inhibitory action on neuronal progenitor cells, and to test the hypothesis that endogenously expressed BMP4 mediates feedback inhibition of neurogenesis in the OE, the following specific aims will be pursued: (1) the actions of BMP4 on progenitor cells in the ORN lineage will be characterized using tissue culture assays to determine effects on progenitor cell proliferation, differentiation, and apoptotic death; (2) the expression patterns of BMP4 mRNA and BMP4 inhibitory proteins will be mapped in OE tissue sections and cultures using in situ hybridization techniques; and (3) a role for endogenous BMP4 as a negative regulator of OE neurogenesis in vivo will be tested in transgenic mice in which BMP4 activity is reduced. By determining whether BMP4 plays a key role in feedback regulation of neurogenesis, and by characterizing the cellular basis of this molecule's action, these studies will provide information that has important implications for our understanding of the molecular basis of growth control in the developing mammalian nervous system. This information should provide insights into possible strategies for effecting cell renewal when neurons have been lost due to disease, injury, or aging.