A Zebrafish Model for a Rare Genetic Disease Reveals a Conserved Role for FBXL3 in the Circadian Clock System

Shir Confino, Talya Dor, Adi Tovin, Yair Wexler, Zohar Ben Moshe Livne, Michaela Kolker, Odelia Pisanty, Sohyun Kathy Park, Nathalie Geyer, Joel Reiter, Shimon Edvardson, Hagar Mor-Shaked, Orly Elpeleg, Daniela Vallone, Lior Appelbaum, Nicholas S. Foulkes, Yoav Gothilf*

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

3 Scopus citations


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.

Original languageEnglish
Article number2373
JournalInternational Journal of Molecular Sciences
Issue number4
StatePublished - 1 Feb 2022


FundersFunder number
German-Israeli Foundation for Scientific Research and DevelopmentI-1320-203.13/2015
Israel Science Foundation961/19, 2462/20


    • Circadian clock
    • FBXL3
    • Rare genetic disease
    • Zebrafish


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