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.
|Sun, Yishan; PaÅŸca, Sergiu P; Portmann, Thomas et al. (2016) A deleterious Nav1.1 mutation selectively impairs telencephalic inhibitory neurons derived from Dravet Syndrome patients. Elife 5:|
|Holloway, Alisha K; Bruneau, Benoit G; Sukonnik, Tatyana et al. (2016) Accelerated Evolution of Enhancer Hotspots in the Mammal Ancestor. Mol Biol Evol 33:1008-18|
|Ypsilanti, AthÃ©na R; Rubenstein, John L R (2016) Transcriptional and epigenetic mechanisms of early cortical development: An examination of how Pax6 coordinates cortical development. J Comp Neurol 524:609-29|
|Zhang, Qiangqiang; Zhang, Yue; Wang, Chunyang et al. (2016) The Zinc Finger Transcription Factor Sp9 Is Required for the Development of Striatopallidal Projection Neurons. Cell Rep 16:1431-44|
|Notwell, James H; Heavner, Whitney E; Darbandi, Siavash Fazel et al. (2016) TBR1 regulates autism risk genes in the developing neocortex. Genome Res 26:1013-22|
|Silberberg, Shanni N; Taher, Leila; Lindtner, Susan et al. (2016) Subpallial Enhancer Transgenic Lines: a Data and Tool Resource to Study Transcriptional Regulation of GABAergic Cell Fate. Neuron 92:59-74|
|Vogt, Daniel; Cho, Kathleen K A; Lee, Anthony T et al. (2015) The parvalbumin/somatostatin ratio is increased in Pten mutant mice and by human PTEN ASD alleles. Cell Rep 11:944-56|
|Hoch, RenÃ©e V; Lindtner, Susan; Price, James D et al. (2015) OTX2 Transcription Factor Controls Regional Patterning within the Medial Ganglionic Eminence and Regional Identity of the Septum. Cell Rep 12:482-94|
|Hoch, RenÃ©e V; Clarke, Jeffrey A; Rubenstein, John L R (2015) Fgf signaling controls the telencephalic distribution of Fgf-expressing progenitors generated in the rostral patterning center. Neural Dev 10:8|
|Vogt, Daniel; Wu, Pei-Rung; Sorrells, Shawn F et al. (2015) Viral-mediated Labeling and Transplantation of Medial Ganglionic Eminence (MGE) Cells for In Vivo Studies. J Vis Exp :|
Showing the most recent 10 out of 47 publications