Neuronal development in the central nervous system is the summation of multiple processes including cellular proliferation, migration, and differentiation. The hepatocyte growth factor/scatter factor (HGF/SF) signaling system via its receptor, MET, possesses multiple activities in cellular proliferation, migration, differentiation and survival. Initial studies demonstrated HGF/SF as a key molecule for cellular migration in the ventral forebrain. New data suggest a role in cell proliferation or survival. Genetically altered mice with reduced HGF/SF-MET signaling levels demonstrate reduced numbers of striatal GABA+ neurons and abnormal behavior. The behavioral phenotype is similar to observations from children afflicted fetal alcohol syndrome, including anxiety, social dysfunction and seizure disorders. Alcohol downregulates HGF/SF levels in many tissues, and exogenous HGF/SF can rescue the signaling deficits. These data suggest that the HGF/SF-MET system is an excellent model for defining the molecular mechanisms underlying the fetal response to alcohol exposure. We will examine the role of the HGF/SF-MET system in three aims:
In Aim 1, we will define the role of HGF/SF in cell proliferation and survival.
In Aim 2, we will investigate the specific actions of HGF/SF-MET system on migrating postmitotic cells.
In Aim 3, we will determine how loss of HGF/SF responsiveness alters phenotypic expression of GABAergic markers. Defining the molecular mechanisms involved in the development of limbic structures is critical to our understanding of the behavioral and neurochemical alterations that result from prenatal drug exposure. ? ? ?
