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A Zebrafish Model for a Rare Genetic Disease Reveals a Conserved Role for FBXL3 in the Circadian Clock System
Shir Confino1, Talya Dor2, Adi Tovin3
1School of Neurobiology, Biochemistry and Biophysics, Faculty of Life Sciences, Tel-Aviv University, Tel-Aviv 6997801, Israel.
Abstract:
The circadian clock, which drives a wide range of bodily rhythms in synchrony with the day-night cycle, is based on a molecular oscillator that ticks with a period of approximately 24 h. Timed proteasomal degradation of clock components is central to the fine-tuning of the oscillator's period. FBXL3 is a protein that functions as a substrate-recognition factor in the E3 ubiquitin ligase complex, and was originally shown in mice to mediate degradation of CRY proteins and thus contribute to the mammalian circadian clock mechanism. By exome sequencing, we have identified a FBXL3 mutation in patients with syndromic developmental delay accompanied by morphological abnormalities and intellectual disability, albeit with a normal sleep pattern. We have investigated the function of FBXL3 in the zebrafish, an excellent model to study both vertebrate development and circadian clock function and, like humans, a diurnal species. Loss of fbxl3a function in zebrafish led to disruption of circadian rhythms of promoter activity and mRNA expression as well as locomotor activity and sleep-wake cycles. However, unlike humans, no morphological effects were evident. These findings point to an evolutionary conserved role for FBXL3 in the circadian clock system across vertebrates and to the acquisition of developmental roles in humans.
Insights
Genetic mutations in FBXL3 disrupt the circadian clock, impacting bodily rhythms. While conserved in zebrafish, FBXL3 gained developmental roles in humans, causing intellectual disability and morphological issues.
Area of Science:
- Chronobiology
- Molecular Biology
- Genetics
Background:
- The circadian clock regulates 24-hour biological rhythms via a molecular oscillator.
- Proteasomal degradation of clock components is crucial for period regulation.
- FBXL3, an E3 ubiquitin ligase factor, degrades CRY proteins, influencing the mammalian circadian clock.
Purpose of the Study:
- Investigate the role of FBXL3 mutations in human developmental disorders.
- Determine the function of FBXL3 in circadian clock mechanisms and development using a zebrafish model.
Main Methods:
- Exome sequencing to identify FBXL3 mutations in patients.
- Functional studies in zebrafish to assess the impact of fbxl3a loss-of-function on circadian rhythms and development.
Main Results:
- Identified a FBXL3 mutation in patients with syndromic developmental delay, intellectual disability, and morphological abnormalities, but normal sleep patterns.
- Loss of fbxl3a in zebrafish disrupted circadian rhythms in gene expression, activity, and sleep-wake cycles.
- Zebrafish lacking fbxl3a did not exhibit morphological abnormalities.
Conclusions:
- FBXL3 plays an evolutionarily conserved role in the vertebrate circadian clock system.
- FBXL3 has acquired developmental roles in humans, distinct from its role in circadian timing.
- FBXL3 mutations highlight a link between circadian clock genes and human developmental disorders.
