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.

National Institute of Health (NIH)
National Institute of Mental Health (NIMH)
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Neurogenesis and Cell Fate Study Section (NCF)
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Panchision, David M
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University of California San Francisco
Schools of Medicine
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Sandberg, Magnus; Taher, Leila; Hu, Jianxin et al. (2018) Genomic analysis of transcriptional networks directing progression of cell states during MGE development. Neural Dev 13:21
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
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