Normal brain function relies on the correct assembly of neural circuits during development. This process starts with the patterning of neural progenitors along the dorsal-ventral and anterior-posterior axes to give rise to distinct subtypes of neurons. A number of key transcription factors have been shown to control the process of neuronal subtype specification. Of these, the homeobox genes Gsx1 and Gsx2 play essential roles in the patterning and differentiation of neuronal cell types that arise from the lateral ganglionic eminence (LGE) progenitors of the mouse telencephalon including striatal projection neurons and olfactory bulb interneurons. Not only is the correct specification of neuronal subtypes crucial for neural circuit formation but also the generation of appropriate numbers of each subtype. Less is known about the mechanisms that control this balance during brain development. In our previous funding period for this grant, we showed that while both Gsx1 and Gsx2 can ultimately specify the same subtypes of neurons, they regulate LGE progenitor maturation differently. Specifically, Gsx2 appears to maintain LGE progenitors in an immature (i.e. stem cell) state while Gsx1 promotes progenitor maturation and transition from the ventricular zone (VZ) to the subventricular zone (SVZ). Accordingly, these results correlate well with the expression of these genes; Gsx2 is largely restricted to VZ progenitors whereas Gsx1 is found enriched in progenitors positioned at the VZ/SVZ boundary. With this application, we plan to combine the mouse genetic expertise of the Campbell lab with the molecular and biochemical expertise of the Gebelein lab to uncover the mechanisms underlying some of the genetic phenotypes our group and others have described for the Gsx mouse mutants. Thus, the studies outlined in this proposal will test the general hypothesis that differential regulation of Gsx2 gen expression and unique protein modifications/interactions underlie the distinct roles that Gsx1 and Gsx2 play in LGE progenitor development. We will test this hypothesis in 3 independent specific aims: 1) To understand the cis-regulatory mechanisms that control Gsx2 expression in LGE progenitors. 2) To determine whether selective MAPK phosphorylation of Gsx1, but not Gsx2, underlies its unique role in regulating LGE progenitor maturation. 3) To study the role of physical interactions between Ascl1 (Mash1) and Gsx2 in the control of LGE progenitor maturation. Our approach will combine the use of mouse, frog and fly genetics with molecular and biochemical approaches to study transcriptional control of neuronal specification in the ventral telencephalon. The unique makeup of our Division of Developmental Biology allows us to take this broad approach and as a result increases our chances of success to both, gain a deeper understanding of how Gsx factors control telencephalic development as well as uncover new gene regulatory mechanisms that may underlie aspects of dysfunction in certain childhood neurological disorders.
The telencephalon is the region of the brain most concerned with cognition and voluntary purposeful movements. The basal ganglia play a crucial role in regulating these brain activities and it is believed that abnormal development and/or function of these brain nuclei leads to childhood neurological disorders including attention deficit hyperactivity disorder (ADHD), obsessive compulsive disorder (OCD) and Tourette's syndrome. At present, we do not fully understand the cellular and molecular mechanisms involved in the development and correct assembly of the basal ganglia. The Campbell lab has been studying the roles that the Gsx homeobox factors play in basal ganglia development using mice as a model system. In this proposal, we will combine the mouse genetics expertise of the Campbell lab with the molecular and biochemical expertise of the Gebelein lab to elucidate novel mechanisms underlying the role of Gsx factors in development of the basal ganglia. Given the similarities between the mouse and human basal ganglia we expect our findings to be highly relevant for a better understanding of the underlying abnormalities in the above mentioned childhood neurological disorders.
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