Changing seasons and circadian rhythms: e“miR”ging roles of miR-132/212

Samuel Fung, University of Toronto, Canada
Zobia Anwer, University of Toronto, Canada
Nick Lowe University of Toronto, Canada

The human body is not designed to forgo sleep. The record for continued wakefulness is 11 days and 25 minutes—the equivalent of binge-watching the Titanic 81 times! Luckily, we have evolved intrinsic time-keeping mechanisms that anticipate day-night cycles. Multiple transcription-translation feedback loops (TTFLs) function ubiquitously to regulate circadian rhythms (CRs) in the 20,000 neurons of the suprachiasmatic nucleus (SCN), a central mammalian brain structure that is the central CR oscillator [1]. The SCN receives daily optic light inputs, adjusts individual neuronal oscillation phases, and orchestrates CRs globally by sending temporal information to peripheral tissues and organs [1,2].

Seasonal variations in the length of days, known as the photoperiod, can profoundly affect animal behaviour and physiology. However, the mechanisms behind SCN seasonal adaptations remain to be explored [3]. Recently, Dr. Hai-Ying (Mary) Cheng’s laboratory at the University of Toronto discovered that day length variations change the SCN’s timing mechanisms and neuronal morphology [3].

Dr. Cheng’s laboratory discovered that the conditional knockout (cKO) of miR-132/212, a non-coding microRNA gene cluster that regulates post-transcriptional gene expression, impacts SCN dendrite spine
morphology and proteomic landscape [3]. They also found that cKO mice adapt faster to shorter “winter” days and adapt slower to longer “summer” days, compared to wild-type mice expressing miR-132/212 [3]. SCN expression of PERIOD2, a key CR regulator, is noticeably enhanced in cKO mice during shorter days and remains tightly synchronized during longer days, unlike wildtype mice [3]. The authors suggest that deletion of miR-132/212 changes CR regulation when manipulating day length [3].

SCN responses to environmental changes, such as crossing time zones, depend on neuronal network properties rather than individual neuron behaviour [3]. With new experiences, neuronal networks exhibit functional and structural plasticity [3]. Quantitative mass spectrometry revealed an attenuated time of day-dependent protein expression within the SCN of cKO mice [3]. Deletion of miR-132/212 affected
a group of proteins regulating cytoskeletal organization, which suggested abnormal neuronal morphology in the SCN [3]. Using morphometric analysis, the authors demonstrated that dendrite spine density
in the SCN was significantly reduced in cKO mice [3]. They confirmed the link between SCN seasonal adaptation and miR-132/212 expression using Syrian hamsters [3]. Here, miR-132/212 levels and dendritic spine density varied according to the photoperiod [3]. Compared to longer days, shorter days elicited a decrease in miR-132/212 levels and dendritic spine density [3].

Surprisingly, the authors found that knocking out another gene, MeCP2, reversed the effects of miR-132/212 ablation by rescuing cKO dendrite spine density to levels observed in wild-type neurons [3]. The authors suggested that miR-132/212 affected dendritic morphology by regulating MeCP2 expression [3]. MeCP2 is a genetic factor for autism and the causative gene for Rett syndrome, a neurodevelopmental disorder that affects females [3]. Interestingly, both disorders are characterized by strong circadian disruptions [3]. How the miR-132/212-MeCP2 pathway contributes to circadian disturbances in these diseases remains unknown [3].

Dr. Cheng’s laboratory elucidated the novel role of miR- 132/212 encoding day length information by modulating SCN neuronal architecture [3]. The findings of this research raise the possibility that structural neuronal changes strongly impact SCN plasticity across seasons [3]. This discovery sheds light on the roles of specific genes in SCN function, which may further illuminate potential therapeutics for sleep-related disorders [3].


  1. 1. Mendoza-Viveros L, Bouchard-Cannon P, Hegazi S, Cheng AH, Pastore S, Cheng HM.Molecular modulators of the circadian clock: lessons from flies and mice. Cell Mol Life Sci.2016;74(6):1035-59.
  2. 2. Ramkisoensing A, Meijer J. Synchronization of biological clock neurons by light and peripheralfeedback systems promotes circadian rhythms and health. Front Neurol. 2015;6:1-16.
  3. 3. Mendoza-Viveros L, Chiang CK, Ong JLK, Hegazi S, Cheng AH, Bouchard-Cannon P, et al. miR-132/212 modulates seasonal adaptation and dendritic morphology of the central circadianclock. Cell Rep. 2017;19(3):505-20.