I hypothesize that understanding the transcriptional networks (enhancers, promoters, and downstream transcription units) regulated by the Nkx2-1 and Lhx6 transcription factors will provide critical information for elucidating the transcriptional circuits underlying the development and function of mammalian MGE-derived cells including cortical interneurons. The medial ganglionic eminence (MGE), a progenitor domain in the embryonic basal telencephalon, generates several telencephalic GABAergic neuronal cell types, including pallidal projection neurons, striatal interneurons (IN) and pallial (cortical and hippocampal) INs. Dysfunction of these neurons is implicated in several types of human neuropsychiatric disorders, including epilepsy, intellectual disability, autism and schizophrenia. The long-term goal of the proposed research is to build upon previous studies in elucidating the transcriptional circuitry that regulates the specification and differentiation of MGE-derived cells. The Nkx2-1 transcription factor (TF) lies at the top of the hierarchy. Loss of Nkx2-1 expression in the ventricular zone (VZ) results in no Lhx6 and Lhx8(7) expression (Sussel et al., 1999;Flandin et al., 2010). Lhx6 promotes cortical IN migration and specification of parvalbumin (PV) and somatostatin (Sst) subtypes (Liodis et al., 2007;Zhao et al., 2008;Neves et al., 2012), Lhx8 promotes differentiation of cholingergic neurons, and Lhx6/8 together regulate differentiation of cortical and striatal INs and globus pallidus (GP) neurons (Flandin et al., 2011;Lopes et al., 2012). Herein, I propose experiments aimed at contributing to deciphering some of the transcriptional networks that drive development of MGE-derived cells using a combination of informatics, biochemistry, mouse genetics and developmental and cell biology. There are four Specific Aims: 1. Identify the transcription factors (TFs) that are expressed during mouse MGE development. 2. Determine the chromosomal binding sites of Nkx2-1 and Lhx6 in mouse MGE cells to identify the directly regulated genes using chromatin immunoprecipitation and DNA sequencing (ChIP-Seq). 3. Characterize a subset of the promoters and enhancers (proximal and distal) regulated by Lhx6 and Nkx2-1. 4. Analysis of the MafB mouse mutant.

Public Health Relevance

The proposed research aims to uncover genetic and biochemical mechanisms underlying development and function of brain structures, such as the cerebral cortex, that control cognition and emotion. Disruption of these genetic processes is implicated in human neurodevelopmental disorders such as autism, intellectual disability, epilepsy and schizophrenia.

Agency
National Institute of Health (NIH)
Institute
National Institute of Mental Health (NIMH)
Type
Research Project (R01)
Project #
2R01MH081880-06
Application #
8631381
Study Section
Neurogenesis and Cell Fate Study Section (NCF)
Program Officer
Panchision, David M
Project Start
2007-12-01
Project End
2019-01-31
Budget Start
2014-02-21
Budget End
2015-01-31
Support Year
6
Fiscal Year
2014
Total Cost
$700,234
Indirect Cost
$250,349
Name
University of California San Francisco
Department
Psychiatry
Type
Schools of Medicine
DUNS #
094878337
City
San Francisco
State
CA
Country
United States
Zip Code
94143
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
Hoch, Renée 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
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 :
Golonzhka, Olga; Nord, Alex; Tang, Paul L F et al. (2015) Pbx Regulates Patterning of the Cerebral Cortex in Progenitors and Postmitotic Neurons. Neuron 88:1192-207
Correa, Stephanie M; Newstrom, David W; Warne, James P et al. (2015) An estrogen-responsive module in the ventromedial hypothalamus selectively drives sex-specific activity in females. Cell Rep 10:62-74
Nord, Alex S; Pattabiraman, Kartik; Visel, Axel et al. (2015) Genomic perspectives of transcriptional regulation in forebrain development. Neuron 85:27-47
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
Thompson, Carol L; Ng, Lydia; Menon, Vilas et al. (2014) A high-resolution spatiotemporal atlas of gene expression of the developing mouse brain. Neuron 83:309-23
Vogt, Daniel; Hunt, Robert F; Mandal, Shyamali et al. (2014) Lhx6 directly regulates Arx and CXCR7 to determine cortical interneuron fate and laminar position. Neuron 82:350-64
Zhao, Yangu; Flandin, Pierre; Vogt, Daniel et al. (2014) Ldb1 is essential for development of Nkx2.1 lineage derived GABAergic and cholinergic neurons in the telencephalon. Dev Biol 385:94-106

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