In:
The Journal of Neuroscience, Society for Neuroscience, Vol. 31, No. 4 ( 2011-01-26), p. 1539-1544
Abstract:
Circadian pacemaking in the suprachiasmatic nucleus (SCN) revolves around a transcriptional/posttranslational feedback loop in which period ( Per ) and cryptochrome ( Cry ) genes are negatively regulated by their protein products. Genetically specified differences in this oscillator underlie sleep and metabolic disorders, and dictate diurnal/nocturnal preference. A critical goal, therefore, is to identify mechanisms that generate circadian phenotypic diversity, through both single gene effects and gene interactions. The individual stabilities of PER or CRY proteins determine pacemaker period, and PER/CRY complexes have been proposed to afford mutual stabilization, although how PER and CRY proteins with contrasting stabilities interact is unknown. We therefore examined interactions between two mutations in male mice: Fbxl3 Afh , which lengthens period by stabilizing CRY, and Csnk1 ε tm1Asil ( CK1 ε Tau ), which destabilizes PER, thereby accelerating the clock. By intercrossing these mutants, we show that the stabilities of CRY and PER are independently regulated, contrary to the expectation of mutual stabilization. Segregation of wild-type and mutant alleles generated a spectrum of periods for rest-activity behavior and SCN bioluminescence rhythms. The mutations exerted independent, additive effects on circadian period, biased toward shorter periods determined by CK1 ε Tau . Notably, Fbxl3 Afh extended the duration of the nadir of the PER2-driven bioluminescence rhythm but CK1 ε Tau reversed this, indicating that despite maintained CRY expression, CK1 ε Tau truncated the interval of negative feedback. These results argue for independent, additive biochemical actions of PER and CRY in circadian control, and complement genome-wide epistatic analyses, seeking to decipher the multigenic control of circadian pacemaking.
Type of Medium:
Online Resource
ISSN:
0270-6474
,
1529-2401
DOI:
10.1523/JNEUROSCI.4107-10.2011
Language:
English
Publisher:
Society for Neuroscience
Publication Date:
2011
detail.hit.zdb_id:
1475274-8
SSG:
12
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