Identification Of Novel Molecular-Genetic Pathways Regulating The Development Of Subpallial Derivatives

The embryonic subpallium produces many different neuronal cell types present throughout the adult telencephalon, including striatal medium spiny neurons (MSN) and cortical interneurons. Dysfunction of either cell type leads to neurological and psychiatric disorders including schizophrenia, epilepsy, and Tourette’s syndrome. Thus, understanding the molecular pathways that regulate their development and function has important implications for understanding disease pathogenesis. This work describes novel methods and genetic factors that expand our ability to characterize the development and function of two major subpallial derivatives: cortical interneurons and striatal MSN. The first part of this thesis characterizes a novel enrichment method for producing parvalbumin-expressing (PV) interneurons from mouse embryonic stem cells. This method, which uses an atypical protein kinase C inhibitor to enhance intermediate neurogenesis, results in a markedly increased ratio of PV+ to somatostatin-expressing interneurons. The findings suggest that the mode of neurogenesis influences cortical interneuron fate determination. Moreover, PV+ interneurons can now be generated in large numbers to study their development, screen for factors that affect their physiology, and used in therapeutic applications. The second part of this thesis examines the function of two putative transcription factors, Zswim5 and Zswim6, in the regulation of striatal development. We show that these genes are expressed in subpallial precursors, and in the case of Zswim6, expressed in the adult striatum. Next, through the generation of Zswim5 and Zswim6 knockout mice, we provide a detailed anatomical, molecular, and behavioral characterization of the resulting phenotypes. Our findings reveal that loss of Zswim6 causes a reduction in striatal volume and morphological changes in MSN. Additionally, these structural changes are associated with alterations in motor behaviors including hyperactivity, impaired rotarod performance, and hyperresponsiveness to amphetamine. These results demonstrate that Zswim6 is indispensable for normal brain development and support findings in human genome-wide association studies that implicate Zswim6 with schizophrenia. Collectively, this dissertation provides novel insights into telencephalic development through the development of in vitro stem cell systems and in vivo disease mouse models that further our ability to test and understand neurological diseases