Genetic Regulation of Telencephalon Development

University Of California, San Francisco, San Francisco CA

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Abstract

There are two general types of telencephalic GABAergic neurons: projection neurons of the basal ganglia and local circuit neurons of cortical structures. Most GABAergic neurons in the adult brain are inhibitory; their dysfunction leads to severe disorders including epilepsy, and abnormalities in their functions are implicated in a range of neuropsychiatric disorders including schizophrenia and autism. Inroads to understanding the genetic control of GABAergic neuron development and function have begun. In the forebrain, the DIxl, 2, 5 & 6 homeobox genes have a central role in this process. We have shown that pairs of these transcription factor-encoding genes are required for regulating early steps in GABAergic neuronal differentiation, whereas individual Dlx genes are required for later steps in differentiation and neural function. Herein, I describe experiments aimed at elucidating some of the molecular mechanisms through which the Dlx genes regulate development and function of telencephalic GABAergic neurons. The experiments include; four approaches to identify Dlx transcriptional target genes; identifying and characterizing enhancer elements that drive expression in specific cells types in the developing subpallium and its derivatives; characterizing the function of selected Dlx regulated genes (e.g.GucylaS, Zfhxib and cMaf); definiting interneuron phenotypes of conditional DIxl, Dlx2, Dlx1/Dlx2 and Dlx5 mutants; and characterizing autism mutant alleles of Dlx2, Lhx6 and other regulators of interneurons using an MGE-transpIant assay.