Header

UZH-Logo

Maintenance Infos

Insights Gained From Zebrafish Models for the Ciliopathy Joubert Syndrome


Rusterholz, Tamara D S; Hofmann, Claudia; Bachmann-Gagescu, Ruxandra (2022). Insights Gained From Zebrafish Models for the Ciliopathy Joubert Syndrome. Frontiers in Genetics, 13:939527.

Abstract

Cilia are quasi-ubiquitous microtubule-based sensory organelles, which play vital roles in signal transduction during development and cell homeostasis. Dysfunction of cilia leads to a group of Mendelian disorders called ciliopathies, divided into different diagnoses according to clinical phenotype constellation and genetic causes. Joubert syndrome (JBTS) is a prototypical ciliopathy defined by a diagnostic cerebellar and brain stem malformation termed the “Molar Tooth Sign” (MTS), in addition to which patients display variable combinations of typical ciliopathy phenotypes such as retinal dystrophy, fibrocystic renal disease, polydactyly or skeletal dystrophy. Like most ciliopathies, JBTS is genetically highly heterogeneous with ∼40 associated genes. Zebrafish are widely used to model ciliopathies given the high conservation of ciliary genes and the variety of specialized cilia types similar to humans. In this review, we compare different existing JBTS zebrafish models with each other and describe their contributions to our understanding of JBTS pathomechanism. We find that retinal dystrophy, which is the most investigated ciliopathy phenotype in zebrafish ciliopathy models, is caused by distinct mechanisms according to the affected gene. Beyond this, differences in phenotypes in other organs observed between different JBTS-mutant models suggest tissue-specific roles for proteins implicated in JBTS. Unfortunately, the lack of systematic assessment of ciliopathy phenotypes in the mutants described in the literature currently limits the conclusions that can be drawn from these comparisons. In the future, the numerous existing JBTS zebrafish models represent a valuable resource that can be leveraged in order to gain further insights into ciliary function, pathomechanisms underlying ciliopathy phenotypes and to develop treatment strategies using small molecules.

Abstract

Cilia are quasi-ubiquitous microtubule-based sensory organelles, which play vital roles in signal transduction during development and cell homeostasis. Dysfunction of cilia leads to a group of Mendelian disorders called ciliopathies, divided into different diagnoses according to clinical phenotype constellation and genetic causes. Joubert syndrome (JBTS) is a prototypical ciliopathy defined by a diagnostic cerebellar and brain stem malformation termed the “Molar Tooth Sign” (MTS), in addition to which patients display variable combinations of typical ciliopathy phenotypes such as retinal dystrophy, fibrocystic renal disease, polydactyly or skeletal dystrophy. Like most ciliopathies, JBTS is genetically highly heterogeneous with ∼40 associated genes. Zebrafish are widely used to model ciliopathies given the high conservation of ciliary genes and the variety of specialized cilia types similar to humans. In this review, we compare different existing JBTS zebrafish models with each other and describe their contributions to our understanding of JBTS pathomechanism. We find that retinal dystrophy, which is the most investigated ciliopathy phenotype in zebrafish ciliopathy models, is caused by distinct mechanisms according to the affected gene. Beyond this, differences in phenotypes in other organs observed between different JBTS-mutant models suggest tissue-specific roles for proteins implicated in JBTS. Unfortunately, the lack of systematic assessment of ciliopathy phenotypes in the mutants described in the literature currently limits the conclusions that can be drawn from these comparisons. In the future, the numerous existing JBTS zebrafish models represent a valuable resource that can be leveraged in order to gain further insights into ciliary function, pathomechanisms underlying ciliopathy phenotypes and to develop treatment strategies using small molecules.

Statistics

Citations

Dimensions.ai Metrics
3 citations in Web of Science®
3 citations in Scopus®
Google Scholar™

Altmetrics

Downloads

42 downloads since deposited on 11 Jul 2022
20 downloads since 12 months
Detailed statistics

Additional indexing

Item Type:Journal Article, refereed, original work
Communities & Collections:04 Faculty of Medicine > Institute of Medical Genetics
07 Faculty of Science > Institute of Molecular Life Sciences
08 Research Priority Programs > Adaptive Brain Circuits in Development and Learning (AdaBD)
Dewey Decimal Classification:570 Life sciences; biology
610 Medicine & health
Uncontrolled Keywords:Genetics (clinical), Genetics, Molecular Medicine, cilia, ciliopathies, Joubert syndrome, zebrafish, retina, CRISPR/Cas9, morpholino (MO), URPP AdaBD
Language:English
Date:30 June 2022
Deposited On:11 Jul 2022 07:28
Last Modified:27 Apr 2024 01:38
Publisher:Frontiers Research Foundation
ISSN:1664-8021
Additional Information:TDSR, CH, and RB-G were supported by SNSF grant PP00P3_198895; TDSR was supported by a PhD student grant from the Zurich Neuroscience Center (ZNZ); RB-G is a member of the University Research Priority Program AdaBD of the University of Zurich
OA Status:Gold
Free access at:PubMed ID. An embargo period may apply.
Publisher DOI:https://doi.org/10.3389/fgene.2022.939527
Related URLs:https://www.frontiersin.org/articles/10.3389/fgene.2022.939527/full#supplementary-material (Publisher)
PubMed ID:35846153
Project Information:
  • : FunderSNSF
  • : Grant IDPP00P3_198895
  • : Project TitleUnderstanding the molecular mechanisms underlying phenotypic variability in ciliopathies
  • : Project Websitehttps://data.snf.ch/grants/grant/198895
  • : FunderUniversity of Zurich
  • : Grant IDURPP AdaBD
  • : Project TitleUniversity Research Priority Program: Adaptive Brain Circuits in Development and Learning (AdaBD)
  • : Project Websitehttps://www.adabd.uzh.ch
  • Content: Published Version
  • Language: English
  • Licence: Creative Commons: Attribution 4.0 International (CC BY 4.0)
  • Content: Supplemental Material
  • Language: English
  • Licence: Creative Commons: Attribution 4.0 International (CC BY 4.0)