Insights Gained From Zebrafish Models for the Ciliopathy Joubert Syndrome

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.

Loss of cilia after neurulation impacts brain development and neuronal activity in larval zebrafish

“…We observed not only size differences for the telencephalon, optic tectum, and hindbrain but also malformations in the cerebellum. These findings align well with the phenotype of patients affected by Joubert’s syndrome (Bachmann-Gagescu et al, 2020; Joubert et al, 1969) which displays absence or underdevelopment of the cerebellar vermis as well as a malformed brain stem (Bashford and Subramanian, 2019; Brancati et al, 2010; Damerla et al, 2015; Ferland et al, 2004; Rachel et al, 2015; Rusterholz et al, 2022). Of note, cerebellar defects have only been described in a single zebrafish mutant so far, carrying a loss of function allele in the Joubert gene arl13b (Rusterholz et al, 2022; Zhu et al, 2020), and have been associated with reduced Wnt signaling.…”

“…These findings align well with the phenotype of patients affected by Joubert’s syndrome (Bachmann-Gagescu et al, 2020; Joubert et al, 1969) which displays absence or underdevelopment of the cerebellar vermis as well as a malformed brain stem (Bashford and Subramanian, 2019; Brancati et al, 2010; Damerla et al, 2015; Ferland et al, 2004; Rachel et al, 2015; Rusterholz et al, 2022). Of note, cerebellar defects have only been described in a single zebrafish mutant so far, carrying a loss of function allele in the Joubert gene arl13b (Rusterholz et al, 2022; Zhu et al, 2020), and have been associated with reduced Wnt signaling. By identifying cerebellar malformation in the elipsa mutant, our findings are therefore opening new avenues for understanding cilia-related control of cerebellar development in Joubert’s syndrome using zebrafish as model system.…”

Shared and unique consequences of Joubert Syndrome gene dysfunction on the zebrafish central nervous system

“…Intriguingly, no CNS phenotype has yet been described in these mutants. In fact, with the exception of the arl13b mutant, CNS phenotypes have generally been little mentioned in zebrafish mutants for ciliary genes (Zhu et al 2020; Rusterholz et al 2022).…”

“…Zebrafish are an excellent model for this purpose. There are currently multiple zebrafish mutants for JBTS-causative genes available which display various JBTS-related phenotypes, including retinal dystrophy, cystic kidneys and spinal curvature (Rusterholz et al 2022). This is also illustrated by a recent report of 12 new zebrafish mutants affecting ciliary transition zone genes, including 8 JBTS-associated genes (Wang et al 2022).…”

In Search of a Target Gene for a Desirable Phenotype in Aquaculture: Genome Editing of Cyprinidae and Salmonidae Species

“…In creating disease models, known mutations in genes that cause particular genetic syndromes in humans are obtained, such as muscle laminopathy [31], Charlevoix-Saguenay spastic ataxia [32], Marfan syndrome [33], Sanfilippo syndrome [34], Joubert syndrome [35],…”