Pluripotent stem cells with the ability to form both neurons and glial cells are present from the earliest stages of embryonic development through senescence. Despite considerable interest, little is known regarding the signaling molecules, growth factors, or the extracellular matrix (ECM) molecules that create the local microenvironment of tissue (neural) stem cells. Recent evidence suggests that in the growth factor and ECM depleted adult CNS, the major stem cell region in the subventricular zone (SVZ) is maintained by noggin-BMP interactions. Like other stem cell """"""""niches"""""""", noggin (produced by the ependyma) promotes neuronal differentiation, while BMP2, 4 produced by neural stem cells antagonize neuronal differentiation activity to maintain the stem cell phenotype. The goal of the current investigation is to determine the role of noggin in producing a neurogenic environment in vivo, in maintaining the SVZ stem cell niche, and in promoting repair following injury. Our initial goal is to produce a line of transgenic mice in which noggin can be expressed in neural stem cells via the CNS restricted nestin second intronic enhancer. Experiments to determine the prenatal and postnatal effects of trensgenic noggin expression will further characterize these animals, the neural stem cell, and the role of noggin in neuronal differentiation. We will determine the potential of noggin to promote CNS repair in two injury models. In the first, the noggin producing ependyma will be removed producing a localized gliosis, then noggin expression induced in SVZ stem cells at various timepoints following injury. In the second, more traditional stroke model, the middle cerebral artery will be occluded and noggin gene expression induced. Because stem cells themselves provide important models to study lineage choice during differentiation, in the longer term, neural stem cells will be derived from trensgenic animals and their differentiation potential determined in vitro and when transplanted to the normal and injured CNS. These studies will provide valuable new data regarding the role of this potent neurogenic molecule during CNS development, in maintaining the regional neural stem cell niche, and will set the stage to directly examine noggin/BMP interactions in additional models of CNS injury and repair. ? ?
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