A Zebrafish Model for a Rare Genetic Disease Reveals a Conserved Role for FBXL3 in the Circadian Clock System
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...
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MDPI AG
2022-02-01
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| Series: | International Journal of Molecular Sciences |
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| Online Access: | https://www.mdpi.com/1422-0067/23/4/2373 |
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| author | 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_facet | 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_sort | Shir Confino |
| collection | DOAJ |
| description | 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 <i>FBXL3</i> 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 <i>fbxl3a</i> 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. |
| first_indexed | 2024-03-09T21:43:21Z |
| format | Article |
| id | doaj.art-b1dc05bb03374457be9362a550e68a97 |
| institution | Directory Open Access Journal |
| issn | 1661-6596 1422-0067 |
| language | English |
| last_indexed | 2024-03-09T21:43:21Z |
| publishDate | 2022-02-01 |
| publisher | MDPI AG |
| record_format | Article |
| series | International Journal of Molecular Sciences |
| spelling | doaj.art-b1dc05bb03374457be9362a550e68a972023-11-23T20:24:35ZengMDPI AGInternational Journal of Molecular Sciences1661-65961422-00672022-02-01234237310.3390/ijms23042373A Zebrafish Model for a Rare Genetic Disease Reveals a Conserved Role for FBXL3 in the Circadian Clock SystemShir Confino0Talya Dor1Adi Tovin2Yair Wexler3Zohar Ben-Moshe Livne4Michaela Kolker5Odelia Pisanty6Sohyun Kathy Park7Nathalie Geyer8Joel Reiter9Shimon Edvardson10Hagar Mor-Shaked11Orly Elpeleg12Daniela Vallone13Lior Appelbaum14Nicholas S. Foulkes15Yoav Gothilf16School of Neurobiology, Biochemistry and Biophysics, Faculty of Life Sciences, Tel-Aviv University, Tel-Aviv 6997801, IsraelPediatric Neurology Unit, Hadassah Medical Center and Faculty of Medicine, Hebrew University of Jerusalem, Jerusalem 91120, IsraelThe Faculty of Life Sciences and the Multidisciplinary Brain Research Center, Bar-Ilan University, Ramat-Gan 5290002, IsraelSchool of Neurobiology, Biochemistry and Biophysics, Faculty of Life Sciences, Tel-Aviv University, Tel-Aviv 6997801, IsraelSchool of Neurobiology, Biochemistry and Biophysics, Faculty of Life Sciences, Tel-Aviv University, Tel-Aviv 6997801, IsraelSchool of Zoology, Faculty of Life Sciences, Tel-Aviv University, Tel-Aviv 6997801, IsraelSchool of Neurobiology, Biochemistry and Biophysics, Faculty of Life Sciences, Tel-Aviv University, Tel-Aviv 6997801, IsraelInstitute of Biological and Chemical Systems, Karlsruhe Institute of Technology, 76344 Eggenstein-Leopoldshafen, GermanyInstitute of Biological and Chemical Systems, Karlsruhe Institute of Technology, 76344 Eggenstein-Leopoldshafen, GermanyPediatric Pulmonary & Sleep Unit, Hadassah Medical Center and Faculty of Medicine, Hebrew University of Jerusalem, Jerusalem 91120, IsraelPediatric Neurology Unit, Hadassah Medical Center and Faculty of Medicine, Hebrew University of Jerusalem, Jerusalem 91120, IsraelDepartment of Genetics, Hadassah Medical Center and Faculty of Medicine, Hebrew University of Jerusalem, Jerusalem 91120, IsraelDepartment of Genetics, Hadassah Medical Center and Faculty of Medicine, Hebrew University of Jerusalem, Jerusalem 91120, IsraelInstitute of Biological and Chemical Systems, Karlsruhe Institute of Technology, 76344 Eggenstein-Leopoldshafen, GermanyThe Faculty of Life Sciences and the Multidisciplinary Brain Research Center, Bar-Ilan University, Ramat-Gan 5290002, IsraelInstitute of Biological and Chemical Systems, Karlsruhe Institute of Technology, 76344 Eggenstein-Leopoldshafen, GermanySchool of Neurobiology, Biochemistry and Biophysics, Faculty of Life Sciences, Tel-Aviv University, Tel-Aviv 6997801, IsraelThe 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 <i>FBXL3</i> 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 <i>fbxl3a</i> 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.https://www.mdpi.com/1422-0067/23/4/2373FBXL3zebrafishcircadian clockrare genetic disease |
| spellingShingle | 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 A Zebrafish Model for a Rare Genetic Disease Reveals a Conserved Role for FBXL3 in the Circadian Clock System International Journal of Molecular Sciences FBXL3 zebrafish circadian clock rare genetic disease |
| title | A Zebrafish Model for a Rare Genetic Disease Reveals a Conserved Role for FBXL3 in the Circadian Clock System |
| title_full | A Zebrafish Model for a Rare Genetic Disease Reveals a Conserved Role for FBXL3 in the Circadian Clock System |
| title_fullStr | A Zebrafish Model for a Rare Genetic Disease Reveals a Conserved Role for FBXL3 in the Circadian Clock System |
| title_full_unstemmed | A Zebrafish Model for a Rare Genetic Disease Reveals a Conserved Role for FBXL3 in the Circadian Clock System |
| title_short | A Zebrafish Model for a Rare Genetic Disease Reveals a Conserved Role for FBXL3 in the Circadian Clock System |
| title_sort | zebrafish model for a rare genetic disease reveals a conserved role for fbxl3 in the circadian clock system |
| topic | FBXL3 zebrafish circadian clock rare genetic disease |
| url | https://www.mdpi.com/1422-0067/23/4/2373 |
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