The Roles of Gsh1 and Gsh2 Genes in Telencephalic Neurogenesis

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The mammalian telencephalon represents the region of the brain that displays the most cellular diversity, particularly with respect to neuronal subtypes. One likely mechanism for generating this diversity is its protracted schedule of neurogenesis. Indeed, telencephalic neurogenesis continues postnatally and even into adulthood, at least in the olfactory bulb and hippocampus. This proposal will examine the role of two homeobox genes, Gsh1 and Gsh2 and their role in the neurogenesis of striatal projection neurons and olfactory bulb interneurons. While striatal neurogenesis occurs exclusively at embryonic time points, olfactory bulb interneurons are generated at both embryonic and postnatal stages. We hypothesize that the Gsh genes specify these two neuronal subtypes at temporally distinct time points and the first 3 aims are designed to test this. In the first aim, we will examine the time windows in which Gsh2 specifies striatal projection neuron progenitors vs their olfactory bulb interneuron counterparts. The second aim will examine the role of Gsh1 in promoting differentiation of telencephalic progenitors. Aim 3 will examine the requirement for Gsh genes in regulating neurogenesis within the postnatal subventricular zone. Recent work has found that Gsh2-expressing progenitors also give rise to oligodendrocytes at perinatal stages. We hypothesize that this only occurs after the down-regulation of Gsh2 at late embryonic and early postnatal stages. Aim 4 will examine this possibility by performing conditional inactivation and overexpression of Gsh2 at perinatal stages birth in vivo and in vitro. Certain neurodevelopmental disorders such as Tourette's syndrome, attention deficit hyperactivity disorder (ADHD) and obsessive compulsive disorder (OCD) are thought to result at least in part from abnormal function/development of the striatum. Additionally, the fact that olfactory bulb interneurons are generated into adulthood has made their progenitors attractive candidates for cellular engineering and cell replacement therapies. Thus greater knowlegde of striatal and olfactory bulb development and the specific roles that Gsh genes play in these processes is likely to provide a better understanding of certain brain disorders and possible brain repair strategies.