Balanced gene regulation by an embryonic brain ncRNA is critical for adult hippocampal GABA circuitry
Open accessAbstract
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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geneM23/isoM19 contained hubs GAD1, GAD2, multiple GABA transporters, interneuron markers RELN and VIP, and DLX1 and DLX6-AS1.
“This module pair contained as hubs the two major GABA synthesizing enzymes (GAD1, GAD2), multiple GABA transporters (SLC6A1, SLC24A3), many other known interneuron markers (RELN, VIP), as well as DLX1 and the lncRNA DLX6-AS1, both critical known regulators of inhibitory neuron development (62).”
From Transcriptome-wide isoform-level dysregulation in ASD, schizophrenia, and bipolar disorder (2018) · cites this paper as [62]
DLX6-AS1 is a known development regulator of interneuron specification.
“the lncRNA DLX6-AS1, a known development regulator of interneuron specification (62)”
From Transcriptome-wide isoform-level dysregulation in ASD, schizophrenia, and bipolar disorder (2018) · cites this paper as [62]
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- Authors
- Bond, A. M., VanGompel, M. J. W., Sametsky, E. A., Clark, M. F., Savage, J. C., Disterhoft, J. F., & Kohtz, J. D.
- Affiliations
- Northwestern University (US)
- Corresponding author
- Kohtz, Jhumku D
- Venue
- Nature Neuroscience
- Published
- 2009-07-20
- Volume
- 12
- Issue
- 8
- Pages
- 1020-1027
- ISSN
- 1097-6256 (ISSN-L)
- 1546-1726
- PMC
- PMC3203213
- OpenAlex
- W2110652874
- Cited by
- 399
- References
- 3
- Citations by year
- 2026: 6 · 2025: 10 · 2024: 22 · 2023: 20 · 2022: 14 · 2021: 24 · 2020: 22 · 2019: 29 · 2018: 25 · 2017: 34 · 2016: 23 · 2015: 30 · 2014: 34 · 2013: 46 · 2012: 19
- FWCI
- 6.17
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Licence
- www.springer.com/tdm (tdm)
- Locations
- Nature Neuroscience (publishedVersion)
- PubMed (publishedVersion)
- Europe PMC (PubMed Central) (acceptedVersion)
- PubMed Central (acceptedVersion)
- Funders
- National Institute on Aging (R01AG017139, R37AG008796)
- National Institute of Mental Health (R01MH047340)
- Eunice Kennedy Shriver National Institute of Child Health and Human Development (R21HD049875, R01HD044745)
- Topics
- Life Sciences › Neuroscience › Developmental Neuroscience › Neurogenesis and neuroplasticity mechanisms
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Cancer Research › Cancer-related molecular mechanisms research
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Developmental Biology and Gene Regulation
- Keywords
- non-coding RNA, Dlx5, Dlx6, homeodomain transcription factor, GABAergic interneurons, hippocampus, dentate gyrus, GAD1, MeCP2, transcriptional regulation, synaptic inhibition, polyadenylated RNA
- MeSH terms
- Animals, gamma-Aminobutyric Acid, Glutamate Decarboxylase, Hippocampus, Interneurons, Mutation, Neural Pathways, Organ Culture Techniques, RNA, Messenger, Mice, Knockout, Homeodomain Proteins, Gene Expression Regulation, Developmental, RNA, Untranslated, Mice, Methyl-CpG-Binding Protein 2
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