Balanced gene regulation by an embryonic brain ncRNA is critical for adult hippocampal GABA circuitry

Allison M. Bond; Michael J.W. Vangompel; Evgeny A. Sametsky; Mary F. Clark; Julie C. Savage; John F. Disterhoft; Jhumku D. Kohtz

doi:10.1038/nn.2371

Balanced gene regulation by an embryonic brain ncRNA is critical for adult hippocampal GABA circuitry

Allison M. Bond, Michael J.W. Vangompel, Evgeny A. Sametsky, Mary F. Clark, Julie C. Savage, John F. Disterhoft, Jhumku D. Kohtz

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

337 Scopus citations

Abstract

Genomic studies demonstrate that, although the majority of the mammalian genome is transcribed, only about 2% of these transcripts are code for proteins. We investigated how the long, polyadenylated Evf2 noncoding RNA regulates transcription of the homeodomain transcription factors DLX5 and DLX6 in the developing mouse forebrain. We found that, in developing ventral forebrain, Evf2 recruited DLX and MECP2 transcription factors to important DNA regulatory elements in the Dlx5/6 intergenic region and controlled Dlx5, Dlx6 and Gad1 expression through trans and cis-acting mechanisms. Evf2 mouse mutants had reduced numbers of GABAergic interneurons in early postnatal hippocampus and dentate gyrus. Although the numbers of GABAergic interneurons and Gad1 RNA levels returned to normal in Evf2 mutant adult hippocampus, reduced synaptic inhibition occurred. These results suggest that noncoding RNA-dependent balanced gene regulation in embryonic brain is critical for proper formation of GABA-dependent neuronal circuitry in adult brain.

Original language	English (US)
Pages (from-to)	1020-1027
Number of pages	8
Journal	Nature neuroscience
Volume	12
Issue number	8
DOIs	https://doi.org/10.1038/nn.2371
State	Published - Aug 2009

Funding

We thank K. Campbell for providing early passage W4 embryonic stem cells, and training and guidance in ES cell manipulation, M. Ekker for Dlx5/6 BAC, P. Lui and N. Copeland for PL253, PL452, bacterial strains and protocols for BAC recombineering, G. Taborn and P. Iannaccone for blastocyst injections, D. Eisentstat for antibody specific to DLX2, A. Joyner for the triple polyadenylation construct, J. Rubenstein for Gad1 probe, and Q. Ma for v-Glut1 probe. We thank K. Jones (Northwestern University) for establishing the conditions for embryonic tissue ChIP. This work was funded by National Institute of Child Health and Human Development grants RO1 HD044745 and R21 HD049875, the Illinois Regenerative Medicine Institute, and an Illinois Excellence in Academic Medicine grant to J.D.K.

ASJC Scopus subject areas

General Neuroscience

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10.1038/nn.2371

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title = "Balanced gene regulation by an embryonic brain ncRNA is critical for adult hippocampal GABA circuitry",

abstract = "Genomic studies demonstrate that, although the majority of the mammalian genome is transcribed, only about 2% of these transcripts are code for proteins. We investigated how the long, polyadenylated Evf2 noncoding RNA regulates transcription of the homeodomain transcription factors DLX5 and DLX6 in the developing mouse forebrain. We found that, in developing ventral forebrain, Evf2 recruited DLX and MECP2 transcription factors to important DNA regulatory elements in the Dlx5/6 intergenic region and controlled Dlx5, Dlx6 and Gad1 expression through trans and cis-acting mechanisms. Evf2 mouse mutants had reduced numbers of GABAergic interneurons in early postnatal hippocampus and dentate gyrus. Although the numbers of GABAergic interneurons and Gad1 RNA levels returned to normal in Evf2 mutant adult hippocampus, reduced synaptic inhibition occurred. These results suggest that noncoding RNA-dependent balanced gene regulation in embryonic brain is critical for proper formation of GABA-dependent neuronal circuitry in adult brain.",

author = "Bond, {Allison M.} and Vangompel, {Michael J.W.} and Sametsky, {Evgeny A.} and Clark, {Mary F.} and Savage, {Julie C.} and Disterhoft, {John F.} and Kohtz, {Jhumku D.}",

note = "Funding Information: We thank K. Campbell for providing early passage W4 embryonic stem cells, and training and guidance in ES cell manipulation, M. Ekker for Dlx5/6 BAC, P. Lui and N. Copeland for PL253, PL452, bacterial strains and protocols for BAC recombineering, G. Taborn and P. Iannaccone for blastocyst injections, D. Eisentstat for antibody specific to DLX2, A. Joyner for the triple polyadenylation construct, J. Rubenstein for Gad1 probe, and Q. Ma for v-Glut1 probe. We thank K. Jones (Northwestern University) for establishing the conditions for embryonic tissue ChIP. This work was funded by National Institute of Child Health and Human Development grants RO1 HD044745 and R21 HD049875, the Illinois Regenerative Medicine Institute, and an Illinois Excellence in Academic Medicine grant to J.D.K.",

year = "2009",

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doi = "10.1038/nn.2371",

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AU - Bond, Allison M.

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AU - Sametsky, Evgeny A.

AU - Clark, Mary F.

AU - Savage, Julie C.

AU - Disterhoft, John F.

AU - Kohtz, Jhumku D.

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N2 - Genomic studies demonstrate that, although the majority of the mammalian genome is transcribed, only about 2% of these transcripts are code for proteins. We investigated how the long, polyadenylated Evf2 noncoding RNA regulates transcription of the homeodomain transcription factors DLX5 and DLX6 in the developing mouse forebrain. We found that, in developing ventral forebrain, Evf2 recruited DLX and MECP2 transcription factors to important DNA regulatory elements in the Dlx5/6 intergenic region and controlled Dlx5, Dlx6 and Gad1 expression through trans and cis-acting mechanisms. Evf2 mouse mutants had reduced numbers of GABAergic interneurons in early postnatal hippocampus and dentate gyrus. Although the numbers of GABAergic interneurons and Gad1 RNA levels returned to normal in Evf2 mutant adult hippocampus, reduced synaptic inhibition occurred. These results suggest that noncoding RNA-dependent balanced gene regulation in embryonic brain is critical for proper formation of GABA-dependent neuronal circuitry in adult brain.

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Balanced gene regulation by an embryonic brain ncRNA is critical for adult hippocampal GABA circuitry

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