Fig. 7.

A model for SIK3 function in circadian neurons. (A) In the sLNvs, SIK3 controls the phosphorylation and therefore the cellular localization of HDAC4. Because HDAC4 localization is rhythmic, we propose that SIK3 activity is under circadian clock control. Alternatively, an HDAC4 phosphatase could be under circadian control. We also propose that HDAC4 regulates the release of a synchronizing cue secreted by the sLNvs that targets the DN1 neurons (red arrow). In the DN1 neurons, SIK3 mediates their synchronization with the sLNvs via phosphorylation of an unknown target protein (green). (B) When SIK3 is down-regulated in the sLNvs, rhythmic HDAC4 phosphorylation and nucleus/cytosol shuttling is lost. Thus, the synchronizing signal is constantly inhibited, leading to poor synchronization of DN1 neurons and thus to fast MDSR and slow SLR. (C) When SIK3 is down-regulated in the DN1 neurons, they are uncoupled from the sLNv synchronizing signal, and their circadian clock runs too fast. As a result, both SLR and MDSR run fast.