Telencephalic GABAergic neurons in the basal ganglia and cerebral cortex have central roles in cognition and emotion. Dysfunction of these neurons contributes to some types of epilepsy, intellectual deficiency, autism and schizophrenia. During development, subpallial progenitors generate most of telencephalic GABAergic neurons, including basal ganglia projections neurons and cortical interneurons6. The Dlx1,2,5&6 homeodomain transcription factors (TF) have central roles for this process7-24. Understanding the genetic circuitry upstream and downstream of the DLX TFs is essential for elucidating the basic mechanisms of telencephalic GABAergic development. To elucidate the genetic circuitry driving the development and function of telencephalic GABAergic progenitors and neurons, we must define the TFs, REs (enhancers and promoters) and the coding regions that they control. We hypothesize that the DLX homeodomain (TF) are at the core of transcriptional circuits, which we call the ?Dlx Pathway?, that regulate the development of most telencephalic GABAergic neurons, including basal ganglia projections neurons and cortical interneurons. We propose experiments aimed at elucidating the network of TFs in the Dlx Pathway that directly regulate genes controlling development of cells generated in the embryonic basal ganglia (ganglionic eminences, GEs). We will use chromatin immunoprecipitation followed by whole genome sequencing (ChIP-Seq) to elucidate in vivo genomic binding sites for TFs upstream and downstream of Dlx1&2 (Aim 1). Analysis of changes in RNA expression in the GEs of Dlx1/2 mutants (Aim 2) will provide evidence for the genes whose expression depends on Dlx function. Histone ChIP-Seq and ATAC- Seq (Aim 3), in conjunction with TF ChIP-Seq, will provide evidence for the locations of regulatory elements (REs; enhancers and promoters) used by Dlx Pathway. Final we will assay RE activity using transgenic methods (Aims 4&5). Elucidating transcription circuits driving telencephalic GABAergic development provides a fundamental framework for understanding the genetic pathways, including the REs, which generate inhibitory neurons. !

Public Health Relevance

Disruption of cerebral cortex and basal ganglia development and function are strongly associated with several major neuropsychiatric disorders, including intellectual deficiency, epilepsy, cerebral palsy, autism and schizophrenia. The experiments proposed in this application aim to elucidate basic mechanisms that underlie normal development of GABAergic neurons of basal ganglia and cerebral cortex. This information will provide a key foundation for understanding the genetic and molecular mechanisms underlying many neuropsychiatric disorders.

Agency
National Institute of Health (NIH)
Institute
National Institute of Mental Health (NIMH)
Type
Research Project (R01)
Project #
5R01MH049428-27
Application #
9625797
Study Section
Neurogenesis and Cell Fate Study Section (NCF)
Program Officer
Panchision, David M
Project Start
1992-06-01
Project End
2022-11-30
Budget Start
2018-12-01
Budget End
2019-11-30
Support Year
27
Fiscal Year
2019
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
Pla, Ramon; Stanco, Amelia; Howard, MacKenzie A et al. (2018) Dlx1 and Dlx2 Promote Interneuron GABA Synthesis, Synaptogenesis, and Dendritogenesis. Cereb Cortex 28:3797-3815
An, Joon-Yong; Lin, Kevin; Zhu, Lingxue et al. (2018) Genome-wide de novo risk score implicates promoter variation in autism spectrum disorder. Science 362:
Xu, Zhejun; Liang, Qifei; Song, Xiaolei et al. (2018) SP8 and SP9 coordinately promote D2-type medium spiny neuron production by activating Six3 expression. Development 145:
Dickel, Diane E; Ypsilanti, Athena R; Pla, Ramón et al. (2018) Ultraconserved Enhancers Are Required for Normal Development. Cell 172:491-499.e15
Li, Jiwen; Wang, Chunyang; Zhang, Zhuangzhi et al. (2018) Transcription Factors Sp8 and Sp9 Coordinately Regulate Olfactory Bulb Interneuron Development. Cereb Cortex 28:3278-3294
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
Yang, Nan; Chanda, Soham; Marro, Samuele et al. (2017) Generation of pure GABAergic neurons by transcription factor programming. Nat Methods 14:621-628
Sun, Yishan; Pa?ca, Sergiu P; Portmann, Thomas et al. (2016) A deleterious Nav1.1 mutation selectively impairs telencephalic inhibitory neurons derived from Dravet Syndrome patients. Elife 5:
Ypsilanti, Athéna 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

Showing the most recent 10 out of 95 publications