Cited by 164Treatment of Major DepressionCancer-related molecular mechanisms researchStress Responses and Cortisol

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Sex-Specific Role for the Long Non-coding RNA LINC00473 in Depression

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Issler, Orna, van der Zee, Yentl Y., Ramakrishnan, Aarthi, Wang, Junshi, Tan, Chunfeng, Loh, Yong-Hwee E., Purushothaman, Immanuel, Walker, Deena M., Lorsch, Zachary S., Hamilton, Peter J., Peña, Catherine J., Flaherty, Erin, Hartley, Brigham J., Torres-Berrío, Angélica, Parise, Eric M., Kronman, Hope, Duffy, Julia E., Estill, Molly S., Calipari, Erin S., Labonté, Benoit, Neve, Rachael L., Tamminga, Carol A., Brennand, Kristen J., Dong, Yan, Shen, Li, Nestler, Eric J.·2020·Neuron

DOI 10.1016/j.neuron.2020.03.023PMC PMC7305959

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Abstract

Depression is a common disorder that affects women at twice the rate of men. Here, we report that long non-coding RNAs (lncRNAs), a recently discovered class of regulatory transcripts, represent about one-third of the differentially expressed genes in the brains of depressed humans and display complex region- and sex-specific patterns of regulation. We identified the primate-specific, neuronal-enriched gene LINC00473 as downregulated in prefrontal cortex (PFC) of depressed females but not males. Using viral-mediated gene transfer to express LINC00473 in adult mouse PFC neurons, we mirrored the human sex-specific phenotype by inducing stress resilience solely in female mice. This sex-specific phenotype was accompanied by changes in synaptic function and gene expression selectively in female mice and, along with studies of human neuron-like cells in culture, implicates LINC00473 as a CREB effector. Together, our studies identify LINC00473 as a female-specific driver of stress resilience that is aberrant in female depression.

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Authors: Issler, O., van der Zee, Y. Y., Ramakrishnan, A., Wang, J., Tan, C., Loh, Y.-H. E., Purushothaman, I., Walker, D. M., Lorsch, Z. S., Hamilton, P. J., Peña, C. J., Flaherty, E., Hartley, B. J., Torres-Berrío, A., Parise, E. M., Kronman, H., Duffy, J. E., Estill, M. S., Calipari, E. S., Labonté, B., Neve, R. L., Tamminga, C. A., Brennand, K. J., Dong, Y., Shen, L., & Nestler, E. J.
Affiliations: Icahn School of Medicine at Mount Sinai (US)
Maastricht University (NL)
University of Pittsburgh (US)
The University of Texas Southwestern Medical Center (US)
Massachusetts General Hospital (US)
Corresponding author: Nestler, Eric J.
ORCID: Issler, Orna
van der Zee, Yentl Y.
Ramakrishnan, Aarthi
Wang, Junshi
Tan, Chunfeng
Loh, Yong-Hwee E.
Walker, Deena M.
Lorsch, Zachary S.
Hamilton, Peter J.
Peña, Catherine J.
Flaherty, Erin
Parise, Eric M.
Kronman, Hope
Estill, Molly S.
Calipari, Erin S.
Neve, Rachael L.
Tamminga, Carol A.
Brennand, Kristen J.
Dong, Yan
Shen, Li
Nestler, Eric J.
Venue: Neuron
Publisher: Elsevier BV
Published: 2020-06
Volume: 106
Issue: 6
Pages: 912-926.e5
ISSN: 0896-6273 (ISSN-L)
DOI: 10.1016/j.neuron.2020.03.023
PMC: PMC7305959
OpenAlex: W3017236879
Cited by: 156
References: 105
Citations by year: 2026: 15 · 2025: 24 · 2024: 25 · 2023: 32 · 2022: 25 · 2021: 27 · 2020: 8
FWCI: 13.79
Type: journal article
Language: en
Open access: bronze
doi.org
Licence: www.elsevier.com/tdm/userlicense/1.0/ (tdm)
www.elsevier.com/legal/tdmrep-license (tdm)
www.elsevier.com/open-access/userlicense/1.0/ (vor, 381 d)
Locations: Neuron (publishedVersion)
PubMed (publishedVersion)
Research Publications (Maastricht University) (publishedVersion, other-oa)
PubMed Central (acceptedVersion)
Research Publications (Maastricht University) (submittedVersion, other-oa)
Funders: Hope for Depression Research Foundation
National Institute of Mental Health
Topics: Health Sciences › Medicine › Pharmacology (medical) › Treatment of Major Depression
Life Sciences › Biochemistry, Genetics and Molecular Biology › Cancer Research › Cancer-related molecular mechanisms research
Life Sciences › Neuroscience › Behavioral Neuroscience › Stress Responses and Cortisol
Keywords: LINC00473, long non-coding RNA, depression, sex differences, stress resilience, prefrontal cortex, depression in women, CREB, synaptic function, neuronal gene expression
MeSH terms: RNA-Seq, Adult, Aged, Aged, 80 and over, Animals, Behavior, Animal, Depression, Major Depressive Disorder, Depressive Disorder, Major, Female, Humans, Male, Mice, Transgenic, Middle Aged, Neurons, Sex Factors, Stress, Psychological, Down-Regulation, Prefrontal Cortex, Mice, Resilience, Psychological, Young Adult, RNA, Long Noncoding

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Sex-Specific Role for the Long Non-coding RNA LINC00473 in Depression

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