Abstract
In genetic screens for Drosophila mutations affecting circadian locomotion rhythms, we have isolated six new alleles of the timeless (tim) gene. Two of these mutations cause short-period rhythms of 21-22 hr in constant darkness, and four result in long-period cycles of 26-28 hr. All alleles are semidominant. Studies of the genetic interactions of some of the tim alleles with period-altering period (per) mutations indicate that these interactions are close to multiplicative; a given allele changes the period length of the genetic background by a fixed percentage, rather than by a fixed number of hours. The tim(L1) allele was studied in molecular detail. The long behavioral period of tim(L1) is reflected in a lengthened molecular oscillation of per and tim RNA and protein levels. The lengthened period is partly caused by delayed nuclear translocation of TIM(L1) protein, shown directly by immunocytochemistry and indirectly by an analysis of the phase response curve of tim(L1) flies.
Full Text
The Full Text of this article is available as a PDF (538.1 KB).
Selected References
These references are in PubMed. This may not be the complete list of references from this article.
- Allada R., White N. E., So W. V., Hall J. C., Rosbash M. A mutant Drosophila homolog of mammalian Clock disrupts circadian rhythms and transcription of period and timeless. Cell. 1998 May 29;93(5):791–804. doi: 10.1016/s0092-8674(00)81440-3. [DOI] [PubMed] [Google Scholar]
- Curtin K. D., Huang Z. J., Rosbash M. Temporally regulated nuclear entry of the Drosophila period protein contributes to the circadian clock. Neuron. 1995 Feb;14(2):365–372. doi: 10.1016/0896-6273(95)90292-9. [DOI] [PubMed] [Google Scholar]
- Dunlap J. C. Genetic analysis of circadian clocks. Annu Rev Physiol. 1993;55:683–728. doi: 10.1146/annurev.ph.55.030193.003343. [DOI] [PubMed] [Google Scholar]
- Dunlap J. C. Genetics and molecular analysis of circadian rhythms. Annu Rev Genet. 1996;30:579–601. doi: 10.1146/annurev.genet.30.1.579. [DOI] [PubMed] [Google Scholar]
- Dunlap J. C. Molecular bases for circadian clocks. Cell. 1999 Jan 22;96(2):271–290. doi: 10.1016/s0092-8674(00)80566-8. [DOI] [PubMed] [Google Scholar]
- Edery I., Zwiebel L. J., Dembinska M. E., Rosbash M. Temporal phosphorylation of the Drosophila period protein. Proc Natl Acad Sci U S A. 1994 Mar 15;91(6):2260–2264. doi: 10.1073/pnas.91.6.2260. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Gekakis N., Saez L., Delahaye-Brown A. M., Myers M. P., Sehgal A., Young M. W., Weitz C. J. Isolation of timeless by PER protein interaction: defective interaction between timeless protein and long-period mutant PERL. Science. 1995 Nov 3;270(5237):811–815. doi: 10.1126/science.270.5237.811. [DOI] [PubMed] [Google Scholar]
- Gekakis N., Staknis D., Nguyen H. B., Davis F. C., Wilsbacher L. D., King D. P., Takahashi J. S., Weitz C. J. Role of the CLOCK protein in the mammalian circadian mechanism. Science. 1998 Jun 5;280(5369):1564–1569. doi: 10.1126/science.280.5369.1564. [DOI] [PubMed] [Google Scholar]
- Hall J. C. Genetics of biological rhythms in drosophila. Adv Genet. 1998;38:135–184. doi: 10.1016/s0065-2660(08)60143-1. [DOI] [PubMed] [Google Scholar]
- Hamblen M. J., White N. E., Emery P. T., Kaiser K., Hall J. C. Molecular and behavioral analysis of four period mutants in Drosophila melanogaster encompassing extreme short, novel long, and unorthodox arrhythmic types. Genetics. 1998 May;149(1):165–178. doi: 10.1093/genetics/149.1.165. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Hardin P. E. Activating inhibitors and inhibiting activators: a day in the life of a fly. Curr Opin Neurobiol. 1998 Oct;8(5):642–647. doi: 10.1016/s0959-4388(98)80093-7. [DOI] [PubMed] [Google Scholar]
- Jin X., Shearman L. P., Weaver D. R., Zylka M. J., de Vries G. J., Reppert S. M. A molecular mechanism regulating rhythmic output from the suprachiasmatic circadian clock. Cell. 1999 Jan 8;96(1):57–68. doi: 10.1016/s0092-8674(00)80959-9. [DOI] [PubMed] [Google Scholar]
- King D. P., Vitaterna M. H., Chang A. M., Dove W. F., Pinto L. H., Turek F. W., Takahashi J. S. The mouse Clock mutation behaves as an antimorph and maps within the W19H deletion, distal of Kit. Genetics. 1997 Jul;146(3):1049–1060. doi: 10.1093/genetics/146.3.1049. [DOI] [PMC free article] [PubMed] [Google Scholar]
- King D. P., Zhao Y., Sangoram A. M., Wilsbacher L. D., Tanaka M., Antoch M. P., Steeves T. D., Vitaterna M. H., Kornhauser J. M., Lowrey P. L. Positional cloning of the mouse circadian clock gene. Cell. 1997 May 16;89(4):641–653. doi: 10.1016/s0092-8674(00)80245-7. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Kloss B., Price J. L., Saez L., Blau J., Rothenfluh A., Wesley C. S., Young M. W. The Drosophila clock gene double-time encodes a protein closely related to human casein kinase Iepsilon. Cell. 1998 Jul 10;94(1):97–107. doi: 10.1016/s0092-8674(00)81225-8. [DOI] [PubMed] [Google Scholar]
- Konopka R. J., Benzer S. Clock mutants of Drosophila melanogaster. Proc Natl Acad Sci U S A. 1971 Sep;68(9):2112–2116. doi: 10.1073/pnas.68.9.2112. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Konopka R. J., Pittendrigh C., Orr D. Reciprocal behaviour associated with altered homeostasis and photosensitivity of Drosophila clock mutants. J Neurogenet. 1989 Sep;6(1):1–10. doi: 10.3109/01677068909107096. [DOI] [PubMed] [Google Scholar]
- Lakin-Thomas P. L., Brody S. Circadian rhythms in Neurospora crassa: interactions between clock mutations. Genetics. 1985 Jan;109(1):49–66. doi: 10.1093/genetics/109.1.49. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Loros J. J., Richman A., Feldman J. F. A recessive circadian clock mutation at the frq locus of Neurospora crassa. Genetics. 1986 Dec;114(4):1095–1110. doi: 10.1093/genetics/114.4.1095. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Marrus S. B., Zeng H., Rosbash M. Effect of constant light and circadian entrainment of perS flies: evidence for light-mediated delay of the negative feedback loop in Drosophila. EMBO J. 1996 Dec 16;15(24):6877–6886. [PMC free article] [PubMed] [Google Scholar]
- Matsumoto A., Tomioka K., Chiba Y., Tanimura T. timrit Lengthens circadian period in a temperature-dependent manner through suppression of PERIOD protein cycling and nuclear localization. Mol Cell Biol. 1999 Jun;19(6):4343–4354. doi: 10.1128/mcb.19.6.4343. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Myers M. P., Wager-Smith K., Rothenfluh-Hilfiker A., Young M. W. Light-induced degradation of TIMELESS and entrainment of the Drosophila circadian clock. Science. 1996 Mar 22;271(5256):1736–1740. doi: 10.1126/science.271.5256.1736. [DOI] [PubMed] [Google Scholar]
- Myers M. P., Wager-Smith K., Wesley C. S., Young M. W., Sehgal A. Positional cloning and sequence analysis of the Drosophila clock gene, timeless. Science. 1995 Nov 3;270(5237):805–808. doi: 10.1126/science.270.5237.805. [DOI] [PubMed] [Google Scholar]
- Naidoo N., Song W., Hunter-Ensor M., Sehgal A. A role for the proteasome in the light response of the timeless clock protein. Science. 1999 Sep 10;285(5434):1737–1741. doi: 10.1126/science.285.5434.1737. [DOI] [PubMed] [Google Scholar]
- Price J. L., Blau J., Rothenfluh A., Abodeely M., Kloss B., Young M. W. double-time is a novel Drosophila clock gene that regulates PERIOD protein accumulation. Cell. 1998 Jul 10;94(1):83–95. doi: 10.1016/s0092-8674(00)81224-6. [DOI] [PubMed] [Google Scholar]
- Rothenfluh A., Young M. W., Saez L. A TIMELESS-independent function for PERIOD proteins in the Drosophila clock. Neuron. 2000 May;26(2):505–514. doi: 10.1016/s0896-6273(00)81182-4. [DOI] [PubMed] [Google Scholar]
- Rutila J. E., Maltseva O., Rosbash M. The timSL mutant affects a restricted portion of the Drosophila melanogaster circadian cycle. J Biol Rhythms. 1998 Oct;13(5):380–392. doi: 10.1177/074873098129000200. [DOI] [PubMed] [Google Scholar]
- Rutila J. E., Suri V., Le M., So W. V., Rosbash M., Hall J. C. CYCLE is a second bHLH-PAS clock protein essential for circadian rhythmicity and transcription of Drosophila period and timeless. Cell. 1998 May 29;93(5):805–814. doi: 10.1016/s0092-8674(00)81441-5. [DOI] [PubMed] [Google Scholar]
- Rutila J. E., Zeng H., Le M., Curtin K. D., Hall J. C., Rosbash M. The timSL mutant of the Drosophila rhythm gene timeless manifests allele-specific interactions with period gene mutants. Neuron. 1996 Nov;17(5):921–929. doi: 10.1016/s0896-6273(00)80223-8. [DOI] [PubMed] [Google Scholar]
- Saez L., Young M. W. Regulation of nuclear entry of the Drosophila clock proteins period and timeless. Neuron. 1996 Nov;17(5):911–920. doi: 10.1016/s0896-6273(00)80222-6. [DOI] [PubMed] [Google Scholar]
- Sehgal A., Price J. L., Man B., Young M. W. Loss of circadian behavioral rhythms and per RNA oscillations in the Drosophila mutant timeless. Science. 1994 Mar 18;263(5153):1603–1606. doi: 10.1126/science.8128246. [DOI] [PubMed] [Google Scholar]
- Suri V., Lanjuin A., Rosbash M. TIMELESS-dependent positive and negative autoregulation in the Drosophila circadian clock. EMBO J. 1999 Feb 1;18(3):675–686. doi: 10.1093/emboj/18.3.675. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Vitaterna M. H., King D. P., Chang A. M., Kornhauser J. M., Lowrey P. L., McDonald J. D., Dove W. F., Pinto L. H., Turek F. W., Takahashi J. S. Mutagenesis and mapping of a mouse gene, Clock, essential for circadian behavior. Science. 1994 Apr 29;264(5159):719–725. doi: 10.1126/science.8171325. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Zerr D. M., Hall J. C., Rosbash M., Siwicki K. K. Circadian fluctuations of period protein immunoreactivity in the CNS and the visual system of Drosophila. J Neurosci. 1990 Aug;10(8):2749–2762. doi: 10.1523/JNEUROSCI.10-08-02749.1990. [DOI] [PMC free article] [PubMed] [Google Scholar]