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
Author Information
Shir Confino: School of Neurobiology, Biochemistry and Biophysics, Faculty of Life Sciences, Tel-Aviv University, Tel-Aviv 6997801, Israel.
Talya Dor: Pediatric Neurology Unit, Hadassah Medical Center and Faculty of Medicine, Hebrew University of Jerusalem, Jerusalem 91120, Israel.
Adi Tovin: The Faculty of Life Sciences and the Multidisciplinary Brain Research Center, Bar-Ilan University, Ramat-Gan 5290002, Israel.
Yair Wexler: School of Neurobiology, Biochemistry and Biophysics, Faculty of Life Sciences, Tel-Aviv University, Tel-Aviv 6997801, Israel.
Zohar Ben-Moshe Livne: School of Neurobiology, Biochemistry and Biophysics, Faculty of Life Sciences, Tel-Aviv University, Tel-Aviv 6997801, Israel.
Michaela Kolker: School of Zoology, Faculty of Life Sciences, Tel-Aviv University, Tel-Aviv 6997801, Israel.
Odelia Pisanty: School of Neurobiology, Biochemistry and Biophysics, Faculty of Life Sciences, Tel-Aviv University, Tel-Aviv 6997801, Israel.
Sohyun Kathy Park: Institute of Biological and Chemical Systems, Karlsruhe Institute of Technology, 76344 Eggenstein-Leopoldshafen, Germany.
Nathalie Geyer: Institute of Biological and Chemical Systems, Karlsruhe Institute of Technology, 76344 Eggenstein-Leopoldshafen, Germany.
Joel Reiter: Pediatric Pulmonary & Sleep Unit, Hadassah Medical Center and Faculty of Medicine, Hebrew University of Jerusalem, Jerusalem 91120, Israel. ORCID
Shimon Edvardson: Pediatric Neurology Unit, Hadassah Medical Center and Faculty of Medicine, Hebrew University of Jerusalem, Jerusalem 91120, Israel.
Hagar Mor-Shaked: Department of Genetics, Hadassah Medical Center and Faculty of Medicine, Hebrew University of Jerusalem, Jerusalem 91120, Israel.
Orly Elpeleg: Department of Genetics, Hadassah Medical Center and Faculty of Medicine, Hebrew University of Jerusalem, Jerusalem 91120, Israel.
Daniela Vallone: Institute of Biological and Chemical Systems, Karlsruhe Institute of Technology, 76344 Eggenstein-Leopoldshafen, Germany.
Lior Appelbaum: The Faculty of Life Sciences and the Multidisciplinary Brain Research Center, Bar-Ilan University, Ramat-Gan 5290002, Israel. ORCID
Nicholas S Foulkes: Institute of Biological and Chemical Systems, Karlsruhe Institute of Technology, 76344 Eggenstein-Leopoldshafen, Germany.
Yoav Gothilf: School of Neurobiology, Biochemistry and Biophysics, Faculty of Life Sciences, Tel-Aviv University, Tel-Aviv 6997801, Israel.
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 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 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.
