How the mammalian brain develops from a proliferating progenitor pool into the most intricate structure in the body is a fundamental question facing modern biology. The work proposed here investigates this question in the telencephalon, the embryonic structure that gives rise to the cerebral cortex and other areas of higher brain function. In addition, these studies will consider the relationship between embryonic neural progenitors and those present in the postnatal brain. Our specific objectives are to understand in depth how the Notch and FGF signaling pathways influence telencephalic progenitors. Previous studies have shown that these pathways play critical roles during progenitor maintenance, proliferation, and differentiation. A defining feature of our approach is an emphasis on characterizing progenitors in vivo. Using our uniquely powerful gain-of-function system, we will genetically modify neural progenitors in the mouse embryo in utero, and examine the fate of those cells during development and in the adult. By combining this approach with in vitro proliferation and developmental potential assays, we will gain insight into the endogenous mechanisms regulating neural progenitors. These studies will also seek to determine specifically which receptors and downstream effectors mediate the effects of Notch signaling in telencephalic progenitors. This work will be complemented by loss-of-function studies focused on understanding the effects of deleting Notch and FGF receptors in telencephalic progenitors. Furthermore, using a novel transgenic approach we will prospectively isolate and characterize telencephalic progenitors containing endogenous Notch activation. By advancing an understanding of the basic mechanisms that regulate mammalian neural progenitors we hope to uncover fundamental principles with potential medical utility. In particular, these studies are likely to facilitate the manipulation of stem cells for therapeutic use in the nervous system and elsewhere.
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|Dang, Louis; Yoon, Keejung; Wang, Mike et al. (2006) Notch3 signaling promotes radial glial/progenitor character in the mammalian telencephalon. Dev Neurosci 28:58-69|