The aim of the current proposal is to determine if transforming growth factor alpha (TGFalpha) plays an important role in the development of the neostriatum and the formation of its connections with the ventral midbrain and neocortex. The neostriatum is a clinically important region as its neurons and connections are selectively vulnerable in neurodegenerative diseases. TGFalpha and EGF, which at the EGF receptor (EGF-R) have been shown to exert trophic activities on striatal, cortical, and substantia nigra neurons in vitro, and also to induce the proliferation of striatal neural stem cells. TGFalpha mRNA has been localized in the postnatal rat neostriatum. EGF-R mRNA has been localized in postnatal rat neostriatum, cortex and substantia nigra. If these molecules play a role in early neuronal proliferation, migration and differentiation of the neostriatum and connecting areas, then one would expect them to be expressed in these brain regions at appropriate stages of development. The ontogeny of EGF-R mRNA and protein and that of TGIalpha mRNA, in the embryonic and postnatal rat striatum, midbrain and cortex will be examined in Specific Aim 1. The cell types that produce TGFalpha and athe EGF-R in these brain areas will be determined by double-labelling in situ hybridization and immunocytochemistry in Specific Aim 2 in order to make specific predictions as to what the functional role of this ligand-receptor pair is.
In Specific Aim 3 and 4 the hypotheses that TGFalpha is required for the normal production and differentiation of cells in the striatum, midbrain and neocortex and the formation of connections between these structures will be tested in mice that do not synthesize TGFalpha.
Specific Aim 3 will test whether cell types that normally express the EGF-R are present in their usual distribution in these brain areas of TGFalpha-deficient mice.
Specific Aim 4 will assess whether athe neostriatum possesses normal anatomical connections in these mice. Finally, in Specific Aim 5, in vitro experiments will be performed to determine if TGFalpha exerts trophic effects on the neuronal phenotypes that normally express HGF-R, in vivo. The goal of the proposed research is to provide information as to the trophic mechanisms by which the neostriatum develops and secondarily, to provide insight as to potential mechanisms of selective neuronal vulnerability in degenerative processes.
