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

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

Research output: Contribution to journal › Article › peer-review

61 Scopus citations

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 inthe 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.

Original language	English (US)
Pages (from-to)	574-587
Number of pages	14
Journal	Neuron
Volume	81
Issue number	3
DOIs	https://doi.org/10.1016/j.neuron.2013.11.024
State	Published - Feb 5 2014
Externally published	Yes

Funding

We are grateful to Michael Wong and Sandra Chang for expert technical help. J. S. acknowledges support from training grant T32 GM007449-36 from the NIGMS and the Ruth Kirschstein NRSA fellowship F31 NS076254-03 from the NINDS. G.P. and H.N acknowledge postdoctoral fellowship support from the European Leukodystrophy Association. This work has been supported by grants to C.D.S. (NS047572) and D.H.R. (NS040511) from the NINDS, to J.L.R.R. (MH049428) from NIMH, and to S.C.B (R01-NS-048528) from NINDS. D.H.R. is an Howard Hughes Medical Institute Investigator.

Funders	Funder number
National Institutes of Health National Institute of Mental Health	R01-NS-048528
National Institute of General Medical Sciences
National Institute of Neurological Disorders and Stroke	R01NS057727
Israel National Road Safety Authority	F31 NS076254-03
Association Européenne contre les Leucodystrophies	NS040511, NS047572, MH049428

ASJC Scopus subject areas

General Neuroscience

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10.1016/j.neuron.2013.11.024

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Silbereis, J. C., Nobuta, H., Tsai, H. H., Heine, V. M., McKinsey, G. L., Meijer, D. H., Howard, M. A., Petryniak, M. A., Potter, G. B., Alberta, J. A., Baraban, S. C., Stiles, C. D., Rubenstein, J. L. R., & Rowitch, D. H. (2014). Olig1 Function Is Required to Repress Dlx1/2 and Interneuron Production in Mammalian Brain. Neuron, 81(3), 574-587. https://doi.org/10.1016/j.neuron.2013.11.024

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title = "Olig1 Function Is Required to Repress Dlx1/2 and Interneuron Production in Mammalian Brain",

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 inthe 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 \textasciitilde{}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.",

author = "Silbereis, \{John C.\} and Hiroko Nobuta and Tsai, \{Hui Hsin\} and Heine, \{Vivi M.\} and McKinsey, \{Gabriel L.\} and Meijer, \{Dimphna H.\} and Howard, \{MacKenzie A.\} and Petryniak, \{Magda A.\} and Potter, \{Gregory B.\} and Alberta, \{John A.\} and Baraban, \{Scott C.\} and Stiles, \{Charles D.\} and Rubenstein, \{John L.R.\} and Rowitch, \{David H.\}",

note = "Funding Information: We are grateful to Michael Wong and Sandra Chang for expert technical help. J. S. acknowledges support from training grant T32 GM007449-36 from the NIGMS and the Ruth Kirschstein NRSA fellowship F31 NS076254-03 from the NINDS. G.P. and H.N acknowledge postdoctoral fellowship support from the European Leukodystrophy Association. This work has been supported by grants to C.D.S. (NS047572) and D.H.R. (NS040511) from the NINDS, to J.L.R.R. (MH049428) from NIMH, and to S.C.B (R01-NS-048528) from NINDS. D.H.R. is an Howard Hughes Medical Institute Investigator. ",

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AU - Heine, Vivi M.

AU - McKinsey, Gabriel L.

AU - Meijer, Dimphna H.

AU - Howard, MacKenzie A.

AU - Petryniak, Magda A.

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AU - Baraban, Scott C.

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Olig1 Function Is Required to Repress Dlx1/2 and Interneuron Production in Mammalian Brain

Abstract

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ASJC Scopus subject areas

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