Oxytocin regulates stress-induced Crf gene transcription through creb-regulated transcription coactivator 3

Benjamin Jurek, David A. Slattery, Yuichi Hiraoka, Ying Liu, Katsuhiko Nishimori, Greti Aguilera, Inga D. Neumann, Erwin H. Van Den Burg

Research output: Contribution to journalArticle

64 Citations (Scopus)

Abstract

The major regulator of the neuroendocrine stress response in the brain is corticotropin releasing factor (CRF), whose transcription is controlled by CREB and its cofactors CRTC2/3 (TORC2/3). Phosphorylated CRTCs are sequestered in the cytoplasm, but rapidly dephosphorylated and translocated into the nucleus following a stressful stimulus. As the stress response is attenuated by oxytocin (OT), we tested whetherOTinterferes with CRTC translocation and, thereby, Crf expression.OT(1 nmol, i.c.v.) delayed the stress-induced increase of nuclear CRTC3 and Crf hnRNA levels in the paraventricular nucleus of male rats and mice, but did not affect either parameter in the absence of the stressor. The increase in Crf hnRNA levels at later time points was parallel to elevated nuclear CRTC2/3 levels. A direct effect of Thr4 Gly7-OT (TGOT) on CRTC3 translocation and Crf expression was found in rat primary hypothalamic neurons, amygdaloid (Ar-5), hypothalamic (H32), and human neuroblastoma (Be(2)M17) cell lines. CRTC3, but not CRCT2, knockdown using siRNA in Be(2)M17 cells prevented the effect of TGOT on Crf hnRNA levels. Chromatin-immunoprecipitation demonstrated that TGOT reduced CRTC3, but not CRTC2, binding to the Crf promoter after 10 min of forskolin stimulation. Together, the results indicate that OT modulates CRTC3 translocation, the binding of CRTC3 to the Crf promoter and, ultimately, transcription of the Crf gene.

Original languageEnglish
Pages (from-to)12248-12260
Number of pages13
JournalJournal of Neuroscience
Volume35
Issue number35
DOIs
Publication statusPublished - 2015 Sep 2

Keywords

  • CRTC3/TORC3
  • Crf
  • Intracellular signaling
  • Oxytocin receptor
  • Stress response

ASJC Scopus subject areas

  • Neuroscience(all)

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    Jurek, B., Slattery, D. A., Hiraoka, Y., Liu, Y., Nishimori, K., Aguilera, G., Neumann, I. D., & Van Den Burg, E. H. (2015). Oxytocin regulates stress-induced Crf gene transcription through creb-regulated transcription coactivator 3. Journal of Neuroscience, 35(35), 12248-12260. https://doi.org/10.1523/JNEUROSCI.1345-14.2015