Development of oligodendrocytes and the generation of myelin internodes within the spinal cord depends upon regional signals derived from the notochord and floor plate and upon neuronal or axonally derived signals. Notochord and floor plate derived signals, in particular sonic hedgehog, appear necessary for specification of the lineage whereas axonal signals appear to be important in both early and late oligodendrocyte development. Neuregulin-1, which is localized in the floor plate as well as in most neurons and their axons, is one of the molecules necessary for normal spinal cord oligodendrocyte development. In the absence of neuregulin-1, O4+ proligodendroblasts do not develop in spinal cord explants. Development of proligodendroblasts can be restored in neuregulin-1 loss-of-function mutants by addition of recombinant neuregulin-1. Oligodendrocytes respond to neuregulins by activating members of the erbB receptor tyrosine kinase family which function as signal transducing heterodimers. We have recently shown that the erbB2 receptor tyrosine kinase is not necessary for the early stages of oligodendrocyte precursor development but is essential for proligodendroblasts to differentiate into galactosylcerebroside positive (GalC+) oligodendrocytes (terminal differentiation). In the presence of erbB2, oligodendrocyte development and myelination are normal. However, in the absence of erbB2 (erbB2-/-) oligodendrocyte development is halted at the proligodendroblast stage with a greater than 10-fold reduction in the number of Ga1C+ oligodendrocytes. Of the minority of erbB2-/- oligodendrocytes that do proceed to differentiate to maturity, these fail to interact with neurites by forming myelin internodes. These data suggest that erbB2 is required for the terminal differentiation of oligodendrocytes and myelination. Together our data and that from other labs supports an integral role for neuregulins and their receptors at multiple stages of oligodendrocyte development. Our overall hypothesis is that neuregulin mediated signals are necessary both at early, prior to terminal differentiation, and late stages of oligodendrocyte development including myelination.
Specific Aim 1 focuses on the function of neuregulin mediated signals in early oligodendrocyte development.
This aim will entail a complete analysis of GRPs, OPCs and proligodendroblasts in mouse spinal cords from neuregulin-1, erbB3, and erbB4 mutant mice.
Specific Aim 2 will determine if neuregulin signals survival versus differentiation in early oligodendrocyte development.
Specific Aim 3 will determine if the effects of erbB2, erbB3 or erbB4 on oligodendrocyte development are cell autonomous.
Specific Aim 4 will determine if neuregulin is an axonal signal for terminal differentiation of oligodendrocytes and myelination.
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