Genetic Regulation of Telencephalon Development

Investigator: John L. Rubenstein, MD, PhD
Sponsor: NIH National Institute of Mental Health

Location(s): United States


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. Telencephalic GABAergic neurons regulate cognition and emotion; their dysfunction is implicated in cognitive disorders (schizophrenia and possibly autism), emotional disorders (anxiety and depression) and epilepsy. Therefore, these studies on the genetic regulation of telencephalic GABAergic neurons provide an important foundation for understanding human gene studies of neuropsychiatric disorders.