title: Unusual circadian locomotor activity and pathophysiology in mutant CRY1 transgenic mice.
abstract: In the widely accepted molecular model underlying mammalian circadian rhythm, cryptochrome proteins (CRYs) play indispensable roles as inhibitive components of the CLOCK-BMAL1-mediated transcriptional-translational negative feedback loop. In order to clarify yet uncovered aspects of mammalian CRYs in vivo, we generated transgenic (Tg) mice ubiquitously overexpressing CRY1 as well as CRY1 having a mutation in the dipeptide motif of cysteine and proline that is conserved beyond evolutional divergence among animal CRYs: cysteine414 of the motif was replaced with alanine (CRY1-AP). The mice overexpressing CRY1 (CRY1 Tg) exhibited robust circadian rhythms of locomotor activity. In sharp contrast, the mice overexpressing CRY1-AP (CRY1-AP Tg) displayed a unique circadian phenotype. Their locomotor free-running periods were very long (around 28h) with rhythm splitting: the bout of activity of CRY1-AP Tg mice was split into two equal components in constant darkness. Moreover, CRY1-AP Tg mice displayed abnormal entrainment behavior: their bout of activity shifted immediately in response to a shift of the light-dark cycles. In addition, we found that CRY1-AP Tg mice showed symptoms characteristic of diabetes mellitus. The results indicate that the motif of CRY1 is crucial to the mammalian clock system and physiology.
authors.affiliation: Research Laboratory for Molecular Genetics, Yamagata University, Yamagata 990-9585, Japan. sikano@med.id.yamagata-u.ac.jp
authors.forename: Satoshi
authors.initials: S
authors.lastname: Okano
authors.forename: Makoto
authors.initials: M
authors.lastname: Akashi
authors.forename: Kiyoshi
authors.initials: K
authors.lastname: Hayasaka
authors.forename: Osamu
authors.initials: O
authors.lastname: Nakajima
mesh_terms: D020816:Amino Acid Motifs / Q000235:genetics; D019943:Amino Acid Substitution / Q000235:genetics; D000818:Animals; D001683:Biological Clocks / Q000235:genetics; D021081:Chronobiology Disorders / Q000235:genetics* / Q000378:metabolism / Q000503:physiopathology; D002940:Circadian Rhythm / Q000235:genetics*; D056931:Cryptochromes; D003624:Darkness; D003920:Diabetes Mellitus / Q000235:genetics / Q000378:metabolism / Q000503:physiopathology; D004195:Disease Models, Animal; D005420:Flavoproteins / Q000235:genetics*; D006948:Hyperkinesis / Q000235:genetics / Q000378:metabolism / Q000503:physiopathology; D008027:Light; D051379:Mice; D008818:Mice, Neurologic Mutants; D008822:Mice, Transgenic; D009043:Motor Activity / Q000235:genetics*; D009154:Mutation / Q000235:genetics*; D010641:Phenotype; D013997:Time Factors
chemical_list: C538964:Cry1 protein, mouse; D056931:Cryptochromes; D005420:Flavoproteins