The present results demonstrate that CK1δ plays a more prominent role than CK1ε in maintaining the period length of circadian rhythmicity in the SCN. This same difference in relative importance of the two closely related kinases has been reported for peripheral tissues (liver and embryonic fibroblasts; 
). Furthermore, the period length of SCN-generated behavioral rhythms is unaffected in CK1ε−/−
. These findings seem consistent with two interpretations. First, CK1ε may be irrelevant to period regulation in the circadian oscillator. Alternatively, both CK1δ and CK1ε may play an important role in the circadian clock, with the role of CK1δ being more prominent in loss-of-function studies, perhaps because of higher levels of expression of CK1δ (as recently reported for fibroblasts; 
Recent work by others strongly supports the latter interpretation, invoking partial functional redundancy between the kinases. Using a pharmacological approach, Walton et al.
showed that an inhibitor of both CK1δ and CK1ε (PF-670462) lengthened the period of mPER2::LUC bioluminescence rhythms of rat fibroblasts in a dose-dependent manner, reaching periods up to 35 hours. In contrast, an inhibitor with relative selectivity for CK1ε (PF-4800567) did not affect circadian period, except at high concentrations that could also affect CK1δ. The simplest explanation, i.e. the effect of PF-670462 on circadian period is due to inhibition of CK1δ alone, is not consistent with our results from a genetic model, as we see only a 2-hour increase in period in CK1δ-deficient liver, fibroblasts, and SCN (
; present results) rather than a 12-hour increase. An alternative explanation is that inhibition of both kinases is needed to see large effects on period. We have been unable to test this idea due to limitations in our ability to generate animals or tissues with simultaneous disruption of both kinases. This idea is supported, however, by recent studies examining the effects of over-expression of a dominant-negative version of CK1ε 
. Over-expression of this dominant-negative construct reduced the activity of both CK1δ and CK1ε, and caused a modest increase in period in wild-type fibroblasts. Remarkably, however, this construct completely disrupted circadian rhythms of mPER2::LUC bioluminescence in CK1δ-deficient fibroblasts 
, further suggesting redundant roles of CK1δ and CK1ε in maintaining 24-hour oscillations. Furthermore, in a recent small-molecule screen, Isojima and colleagues found that a common feature of compounds causing an increase in circadian period was inhibition of CK1δ/CK1ε activity, and RNA interference targeting either kinase lengthened period in human U2 osteosarcoma cells, although reducing expression of CK1δ by RNA interference had a larger effect than knocking down CK1ε 
These results suggest that CK1δ-deficient tissues remain rhythmic, albeit with a longer period, due to the activity of CK1ε. To confirm this apparent functional redundancy between these two kinases in the circadian system, it would be ideal to use a genetic approach to simultaneously disrupt the expression of both CK1δ and CK1ε. Complementary experiments combining genetic and pharmacological approaches to investigate the relative role of the two kinases are also needed.