Olig1 function is required to repress dlx1/2 and interneuron production in Mammalian brain

John C Silbereis; Hiroko Nobuta; Hui-Hsin Tsai; Vivi M Heine; Gabriel L McKinsey; Dimphna H Meijer; Mackenzie A Howard; Magda A Petryniak; Gregory B Potter; John A Alberta; Scott C Baraban; Charles D Stiles; John L R Rubenstein; David H Rowitch

doi:10.1016/j.neuron.2013.11.024

Olig1 function is required to repress dlx1/2 and interneuron production in Mammalian brain

Neuron. 2014 Feb 5;81(3):574-87. doi: 10.1016/j.neuron.2013.11.024.

Authors

Affiliations

¹ Department of Pediatrics, Eli and Edythe Broad Institute for Stem Cell Research and Regeneration Medicine, University of California, San Francisco, San Francisco, CA 94143, USA; Department of Neurosurgery, University of California, San Francisco, San Francisco, CA 94143, USA; Neuroscience Graduate Program, University of California, San Francisco, San Francisco, CA 94143, USA; Howard Hughes Medical Institute, Chevy Chase, MD 20815, USA.
² Department of Pediatrics, Eli and Edythe Broad Institute for Stem Cell Research and Regeneration Medicine, University of California, San Francisco, San Francisco, CA 94143, USA; Department of Neurosurgery, University of California, San Francisco, San Francisco, CA 94143, USA; Howard Hughes Medical Institute, Chevy Chase, MD 20815, USA.
³ Department of Pediatrics, Eli and Edythe Broad Institute for Stem Cell Research and Regeneration Medicine, University of California, San Francisco, San Francisco, CA 94143, USA; Department of Neurosurgery, University of California, San Francisco, San Francisco, CA 94143, USA.
⁴ Neuroscience Graduate Program, University of California, San Francisco, San Francisco, CA 94143, USA; Department of Psychiatry, University of California, San Francisco, San Francisco, CA 94143, USA.
⁵ Department of Cancer Biology, Dana-Farber Cancer Institute, Boston, MA 02115, USA.
⁶ Department of Neurosurgery, University of California, San Francisco, San Francisco, CA 94143, USA.
⁷ Department of Pediatrics, Eli and Edythe Broad Institute for Stem Cell Research and Regeneration Medicine, University of California, San Francisco, San Francisco, CA 94143, USA.
⁸ Department of Psychiatry, University of California, San Francisco, San Francisco, CA 94143, USA.
⁹ Department of Pediatrics, Eli and Edythe Broad Institute for Stem Cell Research and Regeneration Medicine, University of California, San Francisco, San Francisco, CA 94143, USA; Department of Neurosurgery, University of California, San Francisco, San Francisco, CA 94143, USA; Howard Hughes Medical Institute, Chevy Chase, MD 20815, USA. Electronic address: rowitchd@peds.ucsf.edu.

Abstract

Abnormal GABAergic interneuron density, and imbalance of excitatory versus inhibitory tone, is thought to result in epilepsy, neurodevelopmental disorders, and psychiatric disease. Recent studies indicate that interneuron cortical density is determined primarily by the size of the precursor pool in the embryonic telencephalon. However, factors essential for regulating interneuron allocation from telencephalic multipotent precursors are poorly understood. Here we report that Olig1 represses production of GABAergic interneurons throughout the mouse brain. Olig1 deletion in mutant mice results in ectopic expression and upregulation of Dlx1/2 genes in the ventral medial ganglionic eminences and adjacent regions of the septum, resulting in an ∼30% increase in adult cortical interneuron numbers. We show that Olig1 directly represses the Dlx1/2 I12b intergenic enhancer and that Dlx1/2 functions genetically downstream of Olig1. These findings establish Olig1 as an essential repressor of Dlx1/2 and interneuron production in developing mammalian brain.

Publication types

Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't

MeSH terms

Action Potentials / genetics
Action Potentials / physiology
Age Factors
Animals
Basic Helix-Loop-Helix Transcription Factors / genetics
Basic Helix-Loop-Helix Transcription Factors / metabolism*
Brain / cytology*
Brain / embryology
Brain / growth & development
Cell Count
DNA-Binding Proteins / genetics
DNA-Binding Proteins / metabolism
Embryo, Mammalian
Gene Expression Regulation, Developmental / genetics
Gene Expression Regulation, Developmental / physiology*
Glutamate Decarboxylase / metabolism
Homeodomain Proteins / genetics
Homeodomain Proteins / metabolism*
Interneurons / physiology*
Mice
Mice, Inbred C57BL
Mice, Transgenic
Mutation / genetics
Nerve Tissue Proteins / metabolism
Neuropeptides / metabolism
Organ Culture Techniques
Patch-Clamp Techniques
Synapses / physiology
Transcription Factors / genetics
Transcription Factors / metabolism*

Substances

Basic Helix-Loop-Helix Transcription Factors
DNA-Binding Proteins
Distal-less homeobox proteins
Homeodomain Proteins
Nerve Tissue Proteins
Neuropeptides
Olig1 protein, mouse
Sp8 protein, mouse
Transcription Factors
Vax1 protein, mouse
Glutamate Decarboxylase
glutamate decarboxylase 1

Abstract

Publication types

MeSH terms

Substances

Grants and funding