Divergent Roles of Clock Genes in Retinal and Suprachiasmatic Nucleus Circadian Oscillators

Abstract

The retina is both a sensory organ and a self-sustained circadian clock. Gene targeting studies have revealed that mammalian circadian clocks generate molecular circadian rhythms through coupled transcription/translation feedback loops which involve 6 core clock genes, namely Period (Per) 1 and 2, Cryptochrome (Cry) 1 and 2, Clock, and Bmal1 and that the roles of individual clock genes in rhythms generation are tissue-specific. However, the mechanisms of molecular circadian rhythms in the mammalian retina are incompletely understood and the extent to which retinal neural clocks share mechanisms with the suprachiasmatic nucleus (SCN), the central neural clock, is unclear. In the present study, we examined the rhythmic amplitude and period of real-time bioluminescence rhythms in explants of retina from Per1-, Per2-, Per3-, Cry1-, Cry2-, and Clock-deficient mice that carried transgenic PERIOD2::LUCIFERASE (PER2::LUC) or Period1::luciferase (Per1::luc) circadian reporters. Per1-, Cry1- and Clock-deficient retinal and SCN explants showed weakened or disrupted rhythms, with stronger effects in retina compared to SCN. Per2, Per3, and Cry2 were individually dispensable for sustained rhythms in both tissues. Retinal and SCN explants from double knockouts of Cry1 and Cry2 were arrhythmic. Gene effects on period were divergent with reduction in the number of Per1 alleles shortening circadian period in retina, but lengthening it in SCN, and knockout of Per3 substantially shortening retinal clock period, but leaving SCN unaffected. Thus, the retinal neural clock has a unique pattern of clock gene dependence at the tissue level that it is similar in pattern, but more severe in degree, than the SCN neural clock, with divergent clock gene regulation of rhythmic period.

Differential roles for cryptochromes in the mammalian retinal clock

“…Our results indicate that at the level of the retina, this is an oversimplification. This is consistent with emerging data where CRY1 and -2 appear to serve distinct and separate functions (24, 42, 43), including differences in the timing of their genomic interactions (44). It has previously been suggested that the mechanism underlying circadian rhythm generation in the retina differs from that in the SCN.…”

The role of lateral habenula–dorsal raphe nucleus circuits in higher brain functions and psychiatric illness

“…A few other brain regions have also been shown to have the independent capacity to generate circadian rhythms independently of the SCN pacemaker [90]. The best-studied of these regions are the olfactory bulbs [91] and retina [92], but the Hb, and particularly the LHb, has also been shown to generate circadian firing-rate rhythms for at least a few cycles in vitro, and to generate circadian rhythms of clock gene expression [93,94]. The LHb is further linked to the circadian system because it receives a vasopressin-containing projection from the SCN, which plays an important role in conveying circadian information [95,96], and cells in the LHb respond to light input similarly to SCN neurons [93].…”

The retinal clock in mammals: role in health and disease

“…Only one study has extensively explored the rhythmic phenotype of single clock gene knockout in retina. Using several clock-gene-deficient mice, Ruan et al 21 reported that the retinal clock is more vulnerable to clock gene disruption than the SCN. The authors showed that Per1, Cry1, and Clock are each necessary for the expression of molecular circadian rhythms by the retina.…”

“…By contrast, knocking out Per2, Per3, or Cry2 individually does not blunt the rhythm but modulates its period or amplitude. 21 For example, retinal explants from…”