FEEDBACK REGULATION OF NEUROGENESIS IN MAMMALS

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DESCRIPTION (provided by applicant): Understanding the biology of neuron production is of fundamental importance if we are to understand the origins of, and develop therapies for, disabilities of the nervous system. Although much is known about the signals that stimulate neurogenesis in mammals, signals that cause neurogenesis to cease when the nervous system has attained its appropriate size remain poorly understood. Yet negative regulation of neurogenesis is likely to be important not only during development, but also later, when persistence of negative signals may inhibit neuron regeneration. The olfactory epithelium (OE) of the mouse is a unique model system for studying this negative regulation. Many aspects of neurogenesis characteristic of the rest of the nervous system only during embryonic development are recapitulated throughout life in the OE, where neurogenesis proceeds continuously. Moreover, OE neurogenesis is a regulated process that maintains the number of differentiated neurons (olfactory receptor neurons [ORNs]) at a particular level. Studies in vivo and in vitro suggest that a signal, produced by neuronal cells (progenitors and ORNs) within the OE, acts on progenitors to inhibit proliferation and generation of new ORNs. Preliminary experiments indicate that growth and differentiation factor 11 (GDF 11) has characteristics expected of this signal. This idea is supported by the patterns of expression of Gdf11 and its putative receptors; the effects of GDF 11 on cultured OE cells; and the phenotypes of induced mutations in Gdf11 and its inhibitor, follistatin (Fst). To test the hypothesis that GDF11 is a crucial negative regulator of neurogenesis in the OE, three specific aims will be pursued: (1) GDF1 l's action in regulating OE neurogenesis will be elucidated, using genetic and pharmacological approaches in vitro and in vivo; (2) the role of Fst in OE neurogenesis in vivo will be determined using genetic tests; and (3) models for how GDF11 and Fst work together (and potentially with other factors) to achieve feedback regulation of neurogenesis will be developed and tested. These studies will provide insights into the molecular mechanisms by which neuron number -- and therefore, ultimately, function -- are regulated during development and regeneration of the mammalian nervous system.