Transgenic expression of microRNA-181d augments the stress-sensitivity of CD4+CD8+ thymocytes

Serkan Belkaya, Nicolai S C Van Oers

Research output: Contribution to journalArticle

16 Citations (Scopus)

Abstract

Physiological stress resulting from infections, trauma, surgery, alcoholism, malnutrition, and/or pregnancy results in a substantial depletion of immature CD4+CD8+ thymocytes. We previously identified 18 distinct stress-responsive microRNAs (miRs) in the thymus upon systemic stress induced by lipopolysaccharide (LPS) or the synthetic glucocorticoid, dexamethasone (Dex). MiRs are short, non-coding RNAs that play critical roles in the immune system by targeting diverse mRNAs, suggesting that their modulation in the thymus in response to stress could impact thymopoiesis. MiR-181d is one such stress-responsive miR, exhibiting a 15-fold down-regulation in expression. We utilized both transgenic and gene-targeting approaches to study the impact of miR-181d on thymopoiesis under normal and stress conditions. The overexpression of miR-181d in developing thymocytes reduced the total number of immature CD4+CD8+ thymocytes. LPS or Dex injections caused a 4-fold greater loss of these cells when compared with the wild type controls. A knockout mouse was developed to selectively eliminate miR-181d, leaving the closely spaced and contiguous family member miR-181c intact. The targeted elimination of just miR-181d resulted in a thymus stress-responsiveness similar to wild-type mice. These experiments suggest that one or more of three other miR-181 family members have overlapping or compensatory functions. Gene expression comparisons of thymocytes from the wild type versus transgenic mice indicated that miR-181d targets a number of stress, metabolic, and signaling pathways. These findings demonstrate that selected miRs enhance stress-mediated thymic involution in vivo.

Original languageEnglish (US)
JournalPLoS One
Volume9
Issue number1
DOIs
StatePublished - Jan 9 2014

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thymocytes
Thymocytes
MicroRNAs
microRNA
Thymus Gland
gene expression
dexamethasone
lipopolysaccharides
Dexamethasone
Lipopolysaccharides
Thymus
mice
synthetic glucocorticoids
immatures
genetically modified organisms
Untranslated RNA
Physiological Stress
Gene Targeting
gene targeting
alcohol abuse

ASJC Scopus subject areas

  • Agricultural and Biological Sciences(all)
  • Biochemistry, Genetics and Molecular Biology(all)
  • Medicine(all)

Cite this

Transgenic expression of microRNA-181d augments the stress-sensitivity of CD4+CD8+ thymocytes. / Belkaya, Serkan; Van Oers, Nicolai S C.

In: PLoS One, Vol. 9, No. 1, 09.01.2014.

Research output: Contribution to journalArticle

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