The principle goal of this project is to identify the cellular states and signals that control cell types and synapses in the central nervous system. The identification of stem cells in the central nervous system (CNS) has led to the realization that large numbers of stem cells are present during brain development and that they share many differentiation mechanisms with stem cells present in the adult brain. However, we have also shown that CNS stem cells change some differentiation mechanisms as development proceeds. Interestingly, CNS stem cells are adapted to low oxygen concentrations at early stages of development when the vascular system is not functional. This oxygen effect is mediated by erythropoietin. This growth factor is known to be involved in responses to low oxygen. This is why athletes train at high altidudes or raise erythropoietin levels directly. In our work we show that low oxygen and high erythropoietin levels favor the formation of midbrain dopamine neurons. These neurons are at risk in Parkinson?s disease. Others are now exploring the possibility that erythropoietin may be a useful treatment in Parkinson?s disease. We have also explored the action of bone morphogenetic proteins on CNS stem cells. In these studies, we made transgenic mice overexpressing constitutively active forms of the growth factor receptors to define distinct roles for these signals at different steps in CNS development. These distinct effects are a consequence of the action of two different receptors. Our work shows that activating one receptor induces the expression and action of the second. This simple mechanism has important general consequences on the proliferation, identity, differentiation and death of CNS stem cells. The CNS stem cells generate neurons and astrocytes, two of the major cell types found in the brain. We showed that neurons and astrocytes interact through specific secreted proteins to form synapses. This is the first identification of a signal pathway between these two cells that regulates synapse formation. Although we have defined this mechanism in developing cells, it continues to act in the adult brain where it may have an interesting role in responses to injury. This brief summary indicates that work under this project continues to define basic aspects of neural development with potentially important clinical implications.
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