Understanding the biology of neuron production is of fundamental importance if we are to understand the origins of, and develop therapies for, developmental disabilities that affect the nervous system. In the mammalian nervous system, neurogenesis the proliferation of neuronal progenitor cells and differentiation of their progeny into neurons appear to be controlled by both positive factors, which increase proliferation of neuronal progenitor cells and the number of neurons that are made and survive; and negative factors, which decrease neuron number by mechanisms such as inhibiting proliferation and inducing cell death. Recent studies using the mouse olfactory epithelium (OE) model system indicate that Bone Morphogenetic Proteins (BMPs) can act as both positive and negative regulators of neurogenesis. In OE tissue cultures, high concentration of BMPs 2, 4, or 7 cause a decrease in the number of proliferating progenitor cells and block production of neurons. However, a low level of BMP expression is required for neurogenesis to take place in the OE, and low concentrations of BMP4 stimulate neurogenesis in OE cultures. In contrast, BMP7 does not have this dose-dependent positive effect. The mRNAs for Bmps 2, 4, and 7 are expressed in OE and/or its surrounding tissue, and Type I and Type II BMP receptors are expressed there as well, with BMPR-1B being expressed at unusually high levels in OE proper. Together, these findings suggest that BMP actions on neurogenesis are determined by the identity and quantity of BMPs expressed in specific neural regions, as well as the receptor type(s) expressed by neuronal progenitor cells. To understand this complex regulation of neurogenesis by BMPs, three specific aims will be pursued: (1) In vitro assays, using OE cultured from wildtype and BmprIB """"""""knockout"""""""" mice, will be used to determine if BMPR-IB is required for anti-neurogenic effects of BMPs, and whether signaling through individual Type I receptors can mediate pro-versus anti-neurogenic responses. (2) Neurogenesis will be assessed in mice in which BMP function is increased or decreased using transgenes and viruses, to determine if neurogenesis in the OE in vivo will be assessed, by examining Bmp """"""""knockout"""""""" mice in which the functions of individual BMPs are reduced, and by testing novel BMPs for potential actions in OE tissue culture assays.. Altogether, the studies outlined in this proposal will aid in our understanding of the regulation of mammalian nervous system development by BMPs.
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