Reciprocal signaling interactions between differentiating glia and neurons shape many of the salient features of the developing nervous system. These include the consolidation of its dorsal-ventral, anterior-posterior, and medial-lateral axes, the regulation of axon growth and guidance, the control of cell proliferation and survival in functionally-related networks, and the myelination of axons. Among the most dramatic examples of glial-neuron interaction are those related to axon guidance. In this proposal, we address two nuclear proteins that function as key regulators of this process. These proteins - Vax1 and Vax2 - are novel homeodomain transcription factors unique to vertebrate nervous systems. Previous genetic studies in our laboratory have suggested that Vax 1 controls the expression of essential axon guidance cues, including the chemoattractant netrin-1 and the receptor tyrosine kinase EphB3, in a set of specialized glial cells at the ventral anterior midline of the developing forebrain and in the optic nerve. Additional preliminary work is consistent with a similar role for Vax2 in a set of specialized guidance glia in the peripheral nervous system. In the experiments detailed in the five specific aims of this proposal, we will exploit a battery of existing mouse mutants, and generate new mutants, to genetically dissect Vax1 and Vax2 function in the developing CNS and PNS. We will identify the targets of Vax1 action in the astrocyte precursors of optic nerve, and assess the genetic interaction of the Vax1, netrin-1, EphB3 and slit-1 genes in the developing forebrain. We will similarly identify targets of Vax2 action in the developing eye field, and assess the role that this transcription factor plays in establishing the dorsal-ventral axis of the retina. We will also study its function in a subset of peripheral glia (Schwann cells) in developing peripheral nerves. Finally, we will investigate the strong genetic interaction that we have recently observed between the Vax genes in forebrain development. Together, these studies will yield fundamental new insights into the transcriptional regulation of glial-neuron interactions in the developing central and peripheral nervous systems.
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