Virtually all eukaryotic organisms appropriately examined have been shown to possess the capacity for endogenous temporal control and organization. The cellular machinery that generates this ability is known collectively as the biological clock. The importance of a detailed understanding of the circadian clock to our understanding of physical and mental health and to the treatment of mental illness rests on the ubiquity of its influence on human mental and physiological processes. These range from circadian changes in basic physiological functions to the clear involvement of circadian rhythms in human work rest cycles and sleep. Human psychiatric illnesses known to be a direct result of clock malfunction include common forms of manic-depressive illness and insomnia. Extensive research in the past has demonstrated the extent and significance of clock control of gene expression and enzyme activities, but in general little is known regarding how clocks control the metabolism of the cells in which they operate. One salient aspect of this regulation is clock control of mRNA abundance via circadian regulation of DNA transcription. We have used subtractive hybridization in the context of circadian control of gene expression to identity genes that are unequivocally under circadian clock control. Recent studies have proven that these genes are regulated at the level of transcription, thereby establishing that there must exist cis-acting regulatory sequences within or adjacent to these genes that are recognized by clock-control factors. In the proposed studies we will use genetic and biochemical screens to identify and characterize these morning specific clock-control factors. Initial studies identified only genes expressed specifically in the morning. We have begun and will complete the identification of genes expressed specifically at other times of day in order to evaluate the extent of clock control of gene expression throughout the day. Using molecular tools that we have developed, we will carry out experiments designed to determine whether, and if so how, these clock-regulated genes and their products are involved in the mechanism or regulation of the biological clock. Specifically, recent experiments from our lab, and also from Aplysia, suggest that there exist certain clock-critical RNAs made in the early morning, and that these encode, soon after their synthesis, clock-critical proteins. We will continue our analysis of morning specific genes in order to identity the clock-critical gene(s). Overall, these studies are a first step toward mapping out the temporal topology of circadian regulation of gene expression, and toward developing a system where clock control can be studied on a broad scale at the molecular level.

Agency
National Institute of Health (NIH)
Institute
National Institute of Mental Health (NIMH)
Type
Research Project (R01)
Project #
5R01MH044651-06
Application #
2246124
Study Section
Molecular, Cellular, and Developmental Neurobiology Review Committee (MCDN)
Project Start
1989-09-01
Project End
1997-12-31
Budget Start
1995-04-01
Budget End
1995-12-31
Support Year
6
Fiscal Year
1995
Total Cost
Indirect Cost
Name
Dartmouth College
Department
Biochemistry
Type
Schools of Medicine
DUNS #
041027822
City
Hanover
State
NH
Country
United States
Zip Code
03755
Hong, Christian I; Jolma, Ingunn W; Loros, Jennifer J et al. (2008) Simulating dark expressions and interactions of frq and wc-1 in the Neurospora circadian clock. Biophys J 94:1221-32
Gooch, Van D; Mehra, Arun; Larrondo, Luis F et al. (2008) Fully codon-optimized luciferase uncovers novel temperature characteristics of the Neurospora clock. Eukaryot Cell 7:28-37
Zamborszky, Judit; Hong, Christian I; Csikasz Nagy, Attila (2007) Computational analysis of mammalian cell division gated by a circadian clock: quantized cell cycles and cell size control. J Biol Rhythms 22:542-53
Zoltowski, Brian D; Schwerdtfeger, Carsten; Widom, Joanne et al. (2007) Conformational switching in the fungal light sensor Vivid. Science 316:1054-7
Belden, William J; Larrondo, Luis F; Froehlich, Allan C et al. (2007) The band mutation in Neurospora crassa is a dominant allele of ras-1 implicating RAS signaling in circadian output. Genes Dev 21:1494-505
Mehra, Arun; Hong, Christian I; Shi, Mi et al. (2006) Circadian rhythmicity by autocatalysis. PLoS Comput Biol 2:e96
Pregueiro, Antonio M; Liu, Qiuyun; Baker, Christopher L et al. (2006) The Neurospora checkpoint kinase 2: a regulatory link between the circadian and cell cycles. Science 313:644-9
Dunlap, Jay C; Loros, Jennifer J (2006) How fungi keep time: circadian system in Neurospora and other fungi. Curr Opin Microbiol 9:579-87
Elvin, Mark; Loros, Jennifer J; Dunlap, Jay C et al. (2005) The PAS/LOV protein VIVID supports a rapidly dampened daytime oscillator that facilitates entrainment of the Neurospora circadian clock. Genes Dev 19:2593-605
Colot, Hildur V; Loros, Jennifer J; Dunlap, Jay C (2005) Temperature-modulated alternative splicing and promoter use in the Circadian clock gene frequency. Mol Biol Cell 16:5563-71

Showing the most recent 10 out of 56 publications