Genetic compensation for cilia defects in <i>cep290</i> mutants by upregulation of cilia-associated small GTPases

Cárdenas-Rodríguez, Magdalena; Austin‐Tse, Christina; Bergboer, Judith G.M.; Molinari, Elisa; Sugano, Yuya; Bachmann‐Gagescu, Ruxandra; Sayer, John A.; Drummond, Iain A.

doi:10.1242/jcs.258568

Cited by 16 publications

(25 citation statements)

References 95 publications

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“…We interpret rescue of phenotypes resulting from KO of an ARF GAP by an activating mutant of an ARF family GTPase as evidence of their interaction in a common pathway. Work from Cardenas-Rodriguez et al. (2021) showed that, in zebrafish, mutations in Cep290 can result in increased expression of a number of proteins, including ARL3, ARL13B, and UNC119 and that exogenous expression of these same proteins can reverse ciliary phenotypes.…”

Section: Discussionmentioning

confidence: 99%

The ARF GAPs ELMOD1 and ELMOD3 act at the Golgi and cilia to regulate ciliogenesis and ciliary protein traffic

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et al. 2022

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ELMODs are a family of three mammalian paralogs that display GTPase activating protein (GAP) activity towards a uniquely broad array of ADP-ribosylation factor (ARF) family GTPases that includes ARF-like (ARL) proteins. ELMODs are ubiquitously expressed in mammalian tissues, highly conserved across eukaryotes, and ancient in origin, being present in the last eukaryotic common ancestor. We described functions of ELMOD2 in immortalized mouse embryonic fibroblasts (MEFs) in the regulation of cell division, microtubules, ciliogenesis, and mitochondrial fusion. Here, using similar strategies with the paralogs ELMOD1 and ELMOD3, we identify novel functions and locations of these cell regulators and compare them to those of ELMOD2, allowing determination of functional redundancy among the family members. We found strong similarities in phenotypes resulting from deletion of either Elmod1 or Elmod3 and marked differences from those arising in Elmod2 deletion lines. Deletion of either Elmod1 or Elmod3 results in the decreased ability of cells to form primary cilia, loss of a subset of proteins from cilia, and accumulation of some ciliary proteins at the Golgi, predicted to result from compromised traffic from the Golgi to cilia. These phenotypes are reversed upon activating mutant expression of either ARL3 or ARL16, linking their roles to ELMOD1/3 actions.

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Section: Discussionmentioning

confidence: 99%

The ARF GAPs ELMOD1 and ELMOD3 act at the Golgi and cilia to regulate ciliogenesis and ciliary protein traffic

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Dewees

et al. 2022

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“…Such phenotypes may represent off-target toxicity effects and may not be specific to downregulation of the targeted gene. Alternatively, the additional phenotypes seen only in morphants could be explained by compensation mechanisms occurring only in mutants ( Rossi et al, 2015 ; El-Brolosy et al, 2019 ; Cardenas-Rodriguez et al, 2021 ) and/or by rescue of the phenotype in zygotic mutants through presence of maternally deposited mRNA and/or protein in the egg. However, for a small number of mutants, maternal zygotic mutants were generated and these still did not present with CE defects, laterality defects, smaller eyes or hydrocephalus (e.g., cc2d2a , kif7 , talpid3 and cep290 ).…”

Section: Comparison Between Zebrafish Models For Joubert Syndromementioning

confidence: 99%

Insights Gained From Zebrafish Models for the Ciliopathy Joubert Syndrome

2022

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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.

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“…Similarly, while targeting CEP290 ( NPHP6 ), a ciliopathy gene linked to BBS, in zebrafish at the mRNA level resulted in severe cilia-related phenotypes, only a mild defect restricted to photoreceptors was observed in genomic mutants. Interestingly, the authors found that the mild presentation of the later was associated with the upregulation of several genes associated to ciliary function [ 63 ]. Importantly, it has been shown that upregulation of compensatory genes is triggered by mutations that introduce a PTC in a mechanism that relies on NMD [ 64 , 65 ].…”

Section: Discussionmentioning

confidence: 99%

Generation and characterization of Ccdc28b mutant mice links the Bardet-Biedl associated gene with mild social behavioral phenotypes

et al. 2022

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CCDC28B (coiled-coil domain-containing protein 28B) was identified as a modifier in the ciliopathy Bardet-Biedl syndrome (BBS). Our previous work in cells and zebrafish showed that CCDC28B plays a role regulating cilia length in a mechanism that is not completely understood. Here we report the generation of a Ccdc28b mutant mouse using CRISPR/Cas9 (Ccdc28b mut). Depletion of CCDC28B resulted in a mild phenotype. Ccdc28b mut animals i) do not present clear structural cilia affectation, although we did observe mild defects in cilia density and cilia length in some tissues, ii) reproduce normally, and iii) do not develop retinal degeneration or obesity, two hallmark features of reported BBS murine models. In contrast, Ccdc28b mut mice did show clear social interaction defects as well as stereotypical behaviors. This finding is indeed relevant regarding CCDC28B as a modifier of BBS since behavioral phenotypes have been documented in BBS. Overall, this work reports a novel mouse model that will be key to continue evaluating genetic interactions in BBS, deciphering the contribution of CCDC28B to modulate the presentation of BBS phenotypes. In addition, our data underscores a novel link between CCDC28B and behavioral defects, providing a novel opportunity to further our understanding of the genetic, cellular, and molecular basis of these complex phenotypes.

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Genetic compensation for cilia defects in cep290 mutants by upregulation of cilia-associated small GTPases

Cited by 16 publications

References 95 publications

The ARF GAPs ELMOD1 and ELMOD3 act at the Golgi and cilia to regulate ciliogenesis and ciliary protein traffic

The ARF GAPs ELMOD1 and ELMOD3 act at the Golgi and cilia to regulate ciliogenesis and ciliary protein traffic

Insights Gained From Zebrafish Models for the Ciliopathy Joubert Syndrome

Generation and characterization of Ccdc28b mutant mice links the Bardet-Biedl associated gene with mild social behavioral phenotypes

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