We have shown that the earliest precursors for oligodendrocytes (the myelinating cells for the CNS) are located in the ventral ventricular region of the spinal cord adjacent to the floor plate and arise at a particular time in development. The ventral origin of oligodendrocytes appears to depend on local environmental signals. We now propose to define the nature of those signals. Preliminary studies suggest that sonic hedgehog (Shh), and neuregulin (NRG) both appear essential for the development of spinal cord oligodendrocyte precursors. Our working hypothesis is the Shh sets the location and neuregulin sets the timing of early oligodendrocyte development. In the first aim, the role of Shh in the development of spinal cord oligodendrocytes will be defined. We will determine if Shh can induce ectopic oligodendrocytes independently from other ventral cells such as motor neurons in explant cultures of chick dorsal spinal cord. When and where Shh is required for the normal development of oligodendrocytes will be determined in the chick spinal cord using function blocking anti-Shh antibodies, and whether Shh can induce oligodendrocytes in the absence of neurons. In the second aim, when neuregulin activity is required for the development of oligodendrocytes, and whether NRG promotes commitment, proliferation or survival of oligodendrocyte precursors will be determined by analysis of spinal cord explants from neuregulin knockout mice. We will examine when and where NRG is expressed in the developing mouse spinal cord, whether distinct isoforms of neuregulin are capable of supporting the development of oligodendrocytes in vitro and whether neuregulin is """"""""downstream"""""""" of Shh signaling. In the third aim, the spatial and temporal expression of the ErbB2, 3 and 4 neuregulin receptors will be examined in the developing spinal cord, and the functional requirements for each of these receptors in the development of spinal cord oligodendrocytes defined by analysis of ErbB knockout mice. These studies will provide important new information on the mechanisms underlying oligodendrocyte development in the vertebrate CNS, and will lead to novel approaches to achieve remyelination after CNS injury or demyelinating diseases.
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