# Characterizing a new role for timeless in the generation of robust and plastic circadian rhythms

> **NIH NIH R01** · BRANDEIS UNIVERSITY · 2021 · $404,759

## Abstract

Project Summary
Circadian clocks organize cellular, physiological and behavioral timing in 24-hour
cycles. Understanding how circadian rhythms are generated, maintained and
adapted to changing conditions is key. Indeed, several diseases such as cancer and
depression are associated with a misalignment between the circadian clock and the
external environment. The current model postulates that circadian oscillators keep
time by complex transcriptional and post-transcriptional feedback loops. The
circadian component encoded by timeless (tim) has a special place at the center of
the circadian clock architecture. TIM is essential for circadian rhythms and, at the
same time, constitutes an entry point for external signals, such as light and
temperature, into the core circadian machinery.
Recently, we uncovered the existence of several mRNA and protein isoforms
generated from tim by alternative processing. These isoforms are subjected to
different types of regulation and encode proteins with different properties, suggesting
that the mechanisms mediating tim function are more complex than previously
though. Importantly, we found that temperature strongly regulates the relative levels
of the different RNA isoforms produced at a given time, likely by acting directly on tim
pre-mRNA processing. Importantly, we have found that elimination of one isoform
(named tim-s) results in abnormal locomotor activity and circadian rhythms,
demonstrating the importance of this regulation.
This proposal aims to unravel the importance of tim alternative RNA processing for
the robustness and plasticity of the circadian system. In order to do so, we will
first generate flies in which the alternative splicing of tim is locked into one state. This
will allow us to determine the functionality of the different isoforms. We will follow by
characterizing the mode of action of these tim isoforms. Last but not least, we will
determine the mechanisms by which temperature regulates tim alternative splicing.
In sum, this project will illuminate the mechanism of tim alternative splicing and
elucidate the functions of the different tim and per mRNA and protein isoforms.

## Key facts

- **NIH application ID:** 10207663
- **Project number:** 5R01GM125859-03
- **Recipient organization:** BRANDEIS UNIVERSITY
- **Principal Investigator:** Sebastian Kadener
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $404,759
- **Award type:** 5
- **Project period:** 2019-09-15 → 2023-06-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10207663

## Citation

> US National Institutes of Health, RePORTER application 10207663, Characterizing a new role for timeless in the generation of robust and plastic circadian rhythms (5R01GM125859-03). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10207663. Licensed CC0.

---

*[NIH grants dataset](/datasets/nih-grants) · CC0 1.0*