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 transcriptiona 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 #
5R01MH081880-10
Application #
9418627
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
2018-02-01
Budget End
2019-01-31
Support Year
10
Fiscal Year
2018
Total Cost
Indirect Cost
Name
University of California San Francisco
Department
Psychiatry
Type
Schools of Medicine
DUNS #
094878337
City
San Francisco
State
CA
Country
United States
Zip Code
94118
Hu, Jia Sheng; Vogt, Daniel; Lindtner, Susan et al. (2017) Coup-TF1 and Coup-TF2 control subtype and laminar identity of MGE-derived neocortical interneurons. Development 144:2837-2851
Hu, Jia Sheng; Vogt, Daniel; Sandberg, Magnus et al. (2017) Cortical interneuron development: a tale of time and space. Development 144:3867-3878
Chen, Ying-Jiun J; Friedman, Brad A; Ha, Connie et al. (2017) Single-cell RNA sequencing identifies distinct mouse medial ganglionic eminence cell types. Sci Rep 7:45656
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
Sandberg, Magnus; Flandin, Pierre; Silberberg, Shanni et al. (2016) Transcriptional Networks Controlled by NKX2-1 in the Development of Forebrain GABAergic Neurons. Neuron 91:1260-1275
Nord, Alex S; Pattabiraman, Kartik; Visel, Axel et al. (2015) Genomic perspectives of transcriptional regulation in forebrain development. Neuron 85:27-47
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
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 11:944-956
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 :

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