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Quantitative Measurement of the Immune Response and Sleep in Drosophila

Quantitative Measurement of the Immune Response and Sleep in Drosophila

Published on: December 4, 2012

TIMELESS mutation alters phase responsiveness and causes advanced sleep phase.

Philip Kurien¹, Pei-Ken Hsu², Jacy Leon¹

¹Department of Anesthesiology, University of California, San Francisco, CA 94143.

Proceedings of the National Academy of Sciences of the United States of America

|May 30, 2019

Summary

A mutation in the human TIMELESS (hTIM) gene causes familial advanced sleep phase (FASP). This study reveals that nuclear exclusion of TIM destabilizes the circadian clock and alters light entrainment, leading to FASP.

Keywords:

TIMELESS familial advanced sleep phase human genetics mammalian circadian clock regulation

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Area of Science:

Chronobiology
Molecular Biology
Genetics

Background:

Circadian molecular clock components are conserved across species.
The precise function of mammalian Timeless (TIM) in the circadian clock remains unclear.

Purpose of the Study:

To investigate the role of the human TIMELESS (hTIM) gene in familial advanced sleep phase (FASP).
To elucidate the molecular mechanisms underlying hTIM's function in circadian rhythm regulation.

Main Methods:

Generated CRISPR mutant mice for the Tim gene.
Analyzed mutant phenotypes including sleep patterns and photic entrainment.
Investigated TIM protein localization, nuclear accumulation, and interaction with CRY2 in mouse embryonic fibroblasts (MEFs).

Main Results:

A mutation in hTIM identified in FASP patients.
Tim mutant mice displayed FASP with altered photic entrainment but a normal circadian period.
The mutation disrupted TIM nuclear accumulation and its affinity for CRY2, destabilizing the PER/CRY complex.
A shortened circadian period was observed in immature MEFs from mutant mice.

Conclusions:

Nuclear exclusion of TIM destabilizes negative regulators of the circadian clock.
Altered TIM function impacts light entrainment.
Disruption of TIM function can lead to familial advanced sleep phase disorder.