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Title: The Transcriptional Repressor DEC2 Regulates Sleep Length in Mammals
Authors: Ying He et al., with corresponding author Ying-Hui Fu at the University of California at San Francisco
Publication Date: August, 2009
Scientists identified two individuals in a family who slept markedly less (average of 6.25 hours/night compared to 8.06 hours/night) than their other family members and shared the P385R mutation in DEC2. To test that it was this mutation that led to the pattern of short sleeping, the authors generated transgenic models with the P385 mutation and observed their sleep patterns. These transgenic studies confirmed that the P385 mutation in DEC2 results in a phenotype that requires less sleep than wild-type (WT) controls.
The scientists identified a mother and her adult daughter heterozygous for the P385R mutation while sequencing candidate genes from a pool of participants who had participated in a sleep study. Both individuals indicated that, although they went to bed at the same time as other members of their family, they woke up and hour and a half to two hours earlier than the others. The authors used wrist actigraphy over a ten-day period to measure the activity periods of these individuals. This data revealed consistently extended periods of activity in individuals with the P385R mutation.
In Vitro Study
To test the effects of the P385R mutation on the repressive activity of Dec2, the authors compared the activities of WT Dec2 and P385R Dec2 in a luciferase assay. The luciferase assay is a technology that resulted in light being emitted in amounts proportional to rates of transcription of specific genes. The difference in light emission between the WT and P385R groups corresponds to differences in transcription rate. These results demonstrated a decrease in the repressive activity of P385R Dec2 compared to WT Dec2.
In Vivo Studies
The authors generated WT and P385R transgenic mice, as well as P385R transgenic mice in which the endogenous mouse DEC2 orthologs had been removed. P385R transgenic mice demonstrated longer periods of activity than WT mice by 1.2 hours, and P385R mice lacking endogenous DEC2 demonstrated even longer activity periods, lasting 2.5 hours longer than WT controls. Notably, DEC2 knock-out mice slept only slightly more than WT mice, suggesting that the P385R mutation may result in a gain of function rather than a loss of function.
They used electroencephalography (EEG) and electromyography (EMG) to compare sleeping patterns in mice heterozygous for the P385R mutation with WT mice. P385R-DEC2 mice showed significant reductions in time spent in both REM (2%) and non-REM (8%) sleep relative to controls. Additionally, P385R-DEC2 mice demonstrated increased periods of wakefulness relative to WT controls, indicating that their sleep was less continuous. However, EEG data indicate that the depth of subjects' sleep was not different between P385R-DEC2 and WT individuals.
In response to six hours of sleep deprivation, both P385R-DEC2 and WT mice displayed an increase in REM and non-REM sleep. However, these increases were significantly less for the P385R-DEC2 mice than for the WT controls.
The authors extended these results to flies by generating transgenic flies containing either the WT or the P385R mutant form of DEC2 expressed under the control of a mushroom body-specific promoter (the mushroom body controls sleep-like behavior in flies). Consistent with the results of the transgenic mouse studies, flies containing the P385R mutation displayed significantly less sleep-like behavior than controls transgenic for WT DEC2.
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He, Y., Jones, C. R., Fujiki, N., Xu, Y., Guo, B., Holder, J. L., Rossner, M. J., Nishino, S., and Fu, Y. 2009. The Transcriptional Repressor DEC2 Regulates Sleep Length in Mammals. Science. 325: 866-870.
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