title: MicroRNA-9 Modulates Hes1 ultradian oscillations by forming a double-negative feedback loop.
abstract: Short-period (ultradian) oscillations of Hes1, a Notch signaling effector, are essential for maintaining neural progenitors in a proliferative state, while constitutive downregulation of Hes1 leads to neuronal differentiation. Hes1 oscillations are driven by autorepression, coupled with high instability of the protein and mRNA. It is unknown how Hes1 mRNA stability is controlled and furthermore, how cells exit oscillations in order to differentiate. Here, we identify a microRNA, miR-9, as a component of ultradian oscillations. We show that miR-9 controls the stability of Hes1 mRNA and that both miR-9 overexpression and lack of miR-9 dampens Hes1 oscillations. Reciprocally, Hes1 represses the transcription of miR-9, resulting in out-of-phase oscillations. However, unlike the primary transcript, mature miR-9 is very stable and thus accumulates over time. Given that raising miR-9 levels leads to dampening of oscillations, these findings provide support for a self-limiting mechanism whereby cells might terminate Hes1 oscillations and differentiate.
authors: Faculty of Life Sciences, Michael Smith Building, University of Manchester, Oxford Road, Manchester M13 9PT, UK.
authors: Boyan
authors: B
authors: Bonev
authors: Peter
authors: P
authors: Stanley
authors: Nancy
authors: N
authors: Papalopulu
mesh_terms: D000204:Activity Cycles / Q000235:genetics* / Q000502:physiology; D000818:Animals; D051792:Basic Helix-Loop-Helix Proteins / Q000235:genetics* / Q000378:metabolism; D001683:Biological Clocks / Q000235:genetics*; D002478:Cells, Cultured; D025461:Feedback, Physiological / Q000502:physiology; D005786:Gene Expression Regulation; D018398:Homeodomain Proteins / Q000235:genetics* / Q000378:metabolism; D051379:Mice; D035683:MicroRNAs / Q000235:genetics / Q000378:metabolism / Q000502:physiology*; D008954:Models, Biological; D034622:RNA Interference / Q000502:physiology; D012333:RNA, Messenger / Q000378:metabolism; D000072056:Transcription Factor HES-1; D014158:Transcription, Genetic / Q000235:genetics
chemical_list: D051792:Basic Helix-Loop-Helix Proteins; D018398:Homeodomain Proteins; D035683:MicroRNAs; D012333:RNA, Messenger; D000072056:Transcription Factor HES-1; C489734:Hes1 protein, mouse; C551804:MIRN9 microRNA, mouse