Over the past decade, tremendous progress has been made in our understanding of the molecular mechanism of circadian clocks in mammals. Circadian oscillations are generated by a set of genes that form a transcriptional autoregulatory feedback loop. In mammals, there are at least seven different genes that have been proposed as 'core'circadian elements of the clock mechanism. Despite this remarkable progress, it is clear that a significant number of genes that regulate circadian rhythms in mammals remain to be discovered and identified. Forward genetic screens have been the most effective tool for circadian gene discovery, and we have used this approach to screen the mouse genome for circadian rhythm mutants in the Neurogenomics Project in the Center for Functional Genomics at Northwestern University. Over 60 new circadian mutants were identified as part of a large-scale ENU mutagenesis screen to create a mutant mouse resource for nervous system and behavioral phenotypes.
Our specific aims are: 1. To identify the gene responsible for the 'Overtime'circadian period mutant in mouse. We will test the hypothesis that the 'Overtime'mutant represents a novel circadian rhythm gene. 2. To determine the genetic map position of twenty of the most robust circadian mutants isolated in our large- scale mutagenesis screen. To provide a more valuable research tool for the circadian research community, we propose to map 20 new circadian mutants. 3. To characterize and identify the 'swing-shift'mutant which is a novel entrainment mutant in mice. We will clone the 'swing-shift'mutant and test the hypothesis that 'swing-shift'mice have either a molecular or an anatomical lesion in the photic input pathway into the suprachiasmatic nucleus. Characterization of these novel circadian mutants and the identification of the causative genes should provide new insight into the mechanism of the mammalian circadian clock.

Agency
National Institute of Health (NIH)
Institute
National Institute of Mental Health (NIMH)
Type
Research Project (R01)
Project #
5R01MH078024-05
Application #
8149934
Study Section
Biological Rhythms and Sleep Study Section (BRS)
Program Officer
Beckel-Mitchener, Andrea C
Project Start
2007-05-01
Project End
2012-10-31
Budget Start
2011-05-01
Budget End
2012-10-31
Support Year
5
Fiscal Year
2011
Total Cost
$356,875
Indirect Cost
Name
Northwestern University at Chicago
Department
Biology
Type
Schools of Arts and Sciences
DUNS #
160079455
City
Evanston
State
IL
Country
United States
Zip Code
60201
Lee, Ivan T; Chang, Alexander S; Manandhar, Manabu et al. (2015) Neuromedin s-producing neurons act as essential pacemakers in the suprachiasmatic nucleus to couple clock neurons and dictate circadian rhythms. Neuron 85:1086-102
Fan, Junmei; Zeng, Hongkui; Olson, David P et al. (2015) Vasoactive intestinal polypeptide (VIP)-expressing neurons in the suprachiasmatic nucleus provide sparse GABAergic outputs to local neurons with circadian regulation occurring distal to the opening of postsynaptic GABAA ionotropic receptors. J Neurosci 35:1905-20
Partch, Carrie L; Green, Carla B; Takahashi, Joseph S (2014) Molecular architecture of the mammalian circadian clock. Trends Cell Biol 24:90-9
Yoo, Seung-Hee; Mohawk, Jennifer A; Siepka, Sandra M et al. (2013) Competing E3 ubiquitin ligases govern circadian periodicity by degradation of CRY in nucleus and cytoplasm. Cell 152:1091-105
Mohawk, Jennifer A; Green, Carla B; Takahashi, Joseph S (2012) Central and peripheral circadian clocks in mammals. Annu Rev Neurosci 35:445-62
Mohawk, Jennifer A; Takahashi, Joseph S (2011) Cell autonomy and synchrony of suprachiasmatic nucleus circadian oscillators. Trends Neurosci 34:349-58
Lowrey, Phillip L; Takahashi, Joseph S (2011) Genetics of circadian rhythms in Mammalian model organisms. Adv Genet 74:175-230
Bass, Joseph; Takahashi, Joseph S (2010) Circadian integration of metabolism and energetics. Science 330:1349-54
Ko, Caroline H; Yamada, Yujiro R; Welsh, David K et al. (2010) Emergence of noise-induced oscillations in the central circadian pacemaker. PLoS Biol 8:e1000513
Welsh, David K; Takahashi, Joseph S; Kay, Steve A (2010) Suprachiasmatic nucleus: cell autonomy and network properties. Annu Rev Physiol 72:551-77

Showing the most recent 10 out of 15 publications