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D. G. McMahon, G. Ruan; Clock Gene Dependence of Mouse Retinal Circadian Clock. Invest. Ophthalmol. Vis. Sci. 2010;51(13):893.
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Mammalian circadian rhythms are generated by an autoregulatory network of "clock genes" that are expressed in a wide variety of tissues and cells. The effects of clock gene deletion on clock function have been found to be tissue-specific, with the highly coupled central neural clock (suprachiasmatic nucleus, SCN) being more resistant to genetic disruption than peripheral tissue clocks in which there is little evidence of cellular coupling. Here we tested the effects of genetic deletion of canonical clock genes on the function of the retinal biological clock in vitro.
Knockout mice for Per1, Per2, Per3, Cry1, Cry2, and Clock (gifts of D. Weaver, A. Sancar, and S. Reppert) were crossed with luciferase reporter strains and molecular circadian rhythms were measured in retinal whole-mounts as in Ruan et al., 2008.
Retinas from Per1-/-, Cry1-/-, and Clock-/- mice were arrhythmic or showed severely disrupted gene cycling, whereas retinas from Per2-/-, Per3-/- and Cry2-/- mice were robustly rhythmic. In addition, Cry1 gene dosage on a Cry2 KO background affected retinal freerunning period with Cry1+/-Cry2-/- exhibiting a lengthened period of ca. 27 hours compared with ca. 25 hours for Cry1+/+Cry2-/-.
The clock gene dependence of the retinal molecular circadian clock is unique among tissues tested to date. Whereas Per1, Cry1 and Clock are individually dispensable for SCN rhythmicity, their deletion disrupts the retinal clock, similar to peripheral tissue clocks. On the other hand, Per2, which is necessary for peripheral clock function, is dispensable for retinal clock function. These data suggest that the retinal circadian clock may lack the compensatory coupling mechanisms of the SCN neural clock and that it may be more vulnerable to genetic perturbation than the central clock. Supported by NEI R01 EY15815 to DGM.
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