The differentiation of oligodendrocytes from neuroectodermal stem cells in the developing central nervous system is spatially restricted and appears to depend on local factors for environmental cues. This regulation may depend on a variety of factors, some inductive, such as sonic hedgehog, and others repressive, such as notch signaling. In order to understand oligodendrocyte development and attempt to improve recovery following dysmyelination or demyelination, it is important to identify these factors and learn how they interact. We have been studying a possible repressive factors for oligodendrocyte development, bone morphogenetic protein (BMP), members of the transforming growth factor Beta family involved in specification of dorsal tissues, that modulate many diverse aspects of central nervous system development and are also present in the adult. Our studies in tissue culture have shown that BMPs 2 and 4 have stage-specific effects on the oligodendrocyte lineage. In the pre-progenitor or precursor stage, BMP inhibits differentiation to oligodendrocytes and promotes astrogliogenesis. BMP loses this affect after the oligodendrocyte matures. The effect of BMP on oligodendrogliogenesis in vivo has been elusive. We have obtained three types of knockout mice that will enable us to determine the role of BMP in oligodendrogliogenesis and astrogliogenesis. We will employ a neural tube-specific conditional knockout of the most widely expressed BMP receptor, BMPR-IA, a knockout of the BMP-IB receptor and a double knockout in which both receptors are deleted. Preliminary data generated in vitro indicates that the normal BMP-mediated suppression of oligodendrocyte maturation is disrupted in cultures derived from the Bmpr-la knockouts and double knockouts. BMP-mediated astrogliogenesis is only disrupted in the double knockouts suggesting a functional redundancy of the IA and IB receptors. We plan to analyze these three mutants to determine the relative contribution of each of the type I receptors as well as the overall effect of the inhibition of BMP signaling. We hypothesize that the elimination of BMP signaling in vivo will cause ectopic and/or premature appearance of oligodendrocytes concomitant with fewer astrocytes. We will perform immunohistochemistry on sections of brain and spinal cord from the three mutants and controls as well as western blotting to determine the in vivo effects. We will then culture oligodendrocytes from these animals in vitro and determine how BMP regulates oligodendrocyte differentiation and astrocyte formation. We will also look at signaling from BMP through a possible downstream mediator, the Id protein family of inhibitors of differentiation. Our preliminary data suggests that Id expression is altered in the BMP mutants.
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