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
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
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
Stanco, Amelia; Pla, Ramón; Vogt, Daniel et al. (2014) NPAS1 represses the generation of specific subtypes of cortical interneurons. Neuron 84:940-53
Visel, Axel; Taher, Leila; Girgis, Hani et al. (2013) A high-resolution enhancer atlas of the developing telencephalon. Cell 152:895-908
Mandal, Shyamali; Stanco, Amelia; Buys, Emmanuel S et al. (2013) Soluble guanylate cyclase generation of cGMP regulates migration of MGE neurons. J Neurosci 33:16897-914
Arguello, Annie; Yang, XiaoYong; Vogt, Daniel et al. (2013) Dapper antagonist of catenin-1 cooperates with Dishevelled-1 during postsynaptic development in mouse forebrain GABAergic interneurons. PLoS One 8:e67679
Chen, Ying-Jiun J; Vogt, Daniel; Wang, Yanling et al. (2013) Use of "MGE enhancers" for labeling and selection of embryonic stem cell-derived medial ganglionic eminence (MGE) progenitors and neurons. PLoS One 8:e61956
McKinsey, Gabriel L; Lindtner, Susan; Trzcinski, Brett et al. (2013) Dlx1&2-dependent expression of Zfhx1b (Sip1, Zeb2) regulates the fate switch between cortical and striatal interneurons. Neuron 77:83-98
Wang, Bei; Long, Jason E; Flandin, Pierre et al. (2013) Loss of Gsx1 and Gsx2 function rescues distinct phenotypes in Dlx1/2 mutants. J Comp Neurol 521:1561-84

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