The tau mutation in the Syrian hamster resides in the enzyme casein kinase 1 ε (CK1ε), resulting in a dramatic acceleration of wheel-running activity cycles to about 20 hours. tau also impacts growth, energy, metabolism, feeding behavior, and circadian mechanisms underpinning seasonal timing, causing accelerated reproductive and neuroendocrine responses to photoperiodic changes.Modeling and experimental studies suggest that tau acts as a gain of function on specific residues of PER, consistent with hamster studies showing accelerated degradation of PER in the suprachiasmatic nucleus in the early circadian night. We have created null and tau mutants of Ckε in mice. Circadian period lengthens in CK1ε-/-, whereas CK1εtau/tau shortens circadian period of behavior in vivo in a manner nearly identical to that of the Syrian hamster. CK1ε tau/tau also accelerates molecular oscillations in peripheral tissues, demonstrating its global circadian role. CK1εtau acts by promoting degradation of both nuclear and cytoplasmic PERIOD, but not CRYPTOCHROME, proteins. Our studies reveal that tau acts as a gain-of-function mutation, to accelerate degradation of PERIOD proteins. tau has consistent effects in both hamsters and mice on the circadian organization of behavior and metabolism, highlighting the global impact of this mutation on mammalian clockwork in brain and periphery. ©2007 Cold Spring Harbor Laboratory Press.
|Number of pages||10|
|Journal||Cold Spring Harbor Symposia on Quantitative Biology|
|Publication status||Published - 2007|