Smoothened and ARL13B are critical in mouse for superior cerebellar peduncle targeting

Suciu, Sarah K.; Long, Alyssa; Caspary, Tamara

doi:10.1093/genetics/iyab084

Cited by 13 publications

(17 citation statements)

References 99 publications

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“…The most parsimonious interpretation is that Chlamydomonas ARL13 is not acting via its GEF activity through ARL3 to prevent PLD accumulation in cilia. In related observations, mice expressing Arl13b R79Q/R79Q , a derivative with impaired GEF-activity for Arl3, were shown to develop normally ( Suciu et al, 2021 ). Thus, two widely used models for ciliopathies do not recapitulate the grave effects of ARL13b mutations with diminished GEF activity on humans.…”

Section: Resultsmentioning

confidence: 92%

Loss of ARL13 impedes BBSome-dependent cargo export from Chlamydomonas cilia

Dai

Gui

Alkhofash

et al. 2022

Journal of Cell Biology

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The GTPase Arl13b participates in ciliary protein transport, but its contribution to intraflagellar transport (IFT), the main motor-based protein shuttle of cilia, remains largely unknown. Chlamydomonas arl13 mutant cilia were characterized by both abnormal reduction and accumulation of select membrane-associated proteins. With respect to the latter, a similar set of proteins including phospholipase D (PLD) also accumulated in BBSome-deficient cilia. IFT and BBSome traffic were apparently normal in arl13. However, transport of PLD, which in control cells moves by BBSome-dependent IFT, was impaired in arl13, causing PLD to accumulate in cilia. ARL13 only rarely and transiently traveled by IFT, indicating that it is not a co-migrating adapter securing PLD to IFT trains. In conclusion, the loss of Chlamydomonas ARL13 impedes BBSome-dependent protein transport, resulting in overlapping biochemical defects in arl13 and bbs mutant cilia.

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Section: Resultsmentioning

confidence: 92%

Loss of ARL13 impedes BBSome-dependent cargo export from Chlamydomonas cilia

Dai

Gui

Alkhofash

et al. 2022

Journal of Cell Biology

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“…This work found that in arl13b morphant (and mutant) larvae, the number of cerebellar granule cells was reduced and the development of Purkinje cells was also affected, anomalies that were linked to defective WNT signaling. Of note, the described central nervous system phenotypes were relatively mild compared to the anomalies found in mouse models for Arl13b (Higginbotham et al, 2012;Suciu et al, 2021) or in human patients harboring ARL13B mutations (Cantagrel et al, 2008;Thomas et al, 2015). No other studies have described cerebellar anomalies in zebrafish JBTS models yet, whereby it remains unclear how thoroughly the central nervous system has been analyzed in the published zebrafish JBTS models to date.…”

Section: Comparison Between Zebrafish Mutants In Joubert Syndrome Genesmentioning

confidence: 94%

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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“…Dendrogram based on [130] and [422] 458]. While the molecular mechanisms causing scp misrouting are incompletely characterized, the ciliary axoneme protein Arl13b regulates scp guidance, which relies on non-cell autonomous Hedgehog signaling [459]. Changes in ARL13B expression cause abnormalities in growth cone dynamics and axonal tract development [458,460].…”

Section: The Cerebellar Nuclei and Joubert Syndromementioning

confidence: 99%

Cerebellum Lecture: the Cerebellar Nuclei—Core of the Cerebellum

et al. 2023

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The cerebellum is a key player in many brain functions and a major topic of neuroscience research. However, the cerebellar nuclei (CN), the main output structures of the cerebellum, are often overlooked. This neglect is because research on the cerebellum typically focuses on the cortex and tends to treat the CN as relatively simple output nuclei conveying an inverted signal from the cerebellar cortex to the rest of the brain. In this review, by adopting a nucleocentric perspective we aim to rectify this impression. First, we describe CN anatomy and modularity and comprehensively integrate CN architecture with its highly organized but complex afferent and efferent connectivity. This is followed by a novel classification of the specific neuronal classes the CN comprise and speculate on the implications of CN structure and physiology for our understanding of adult cerebellar function. Based on this thorough review of the adult literature we provide a comprehensive overview of CN embryonic development and, by comparing cerebellar structures in various chordate clades, propose an interpretation of CN evolution. Despite their critical importance in cerebellar function, from a clinical perspective intriguingly few, if any, neurological disorders appear to primarily affect the CN. To highlight this curious anomaly, and encourage future nucleocentric interpretations, we build on our review to provide a brief overview of the various syndromes in which the CN are currently implicated. Finally, we summarize the specific perspectives that a nucleocentric view of the cerebellum brings, move major outstanding issues in CN biology to the limelight, and provide a roadmap to the key questions that need to be answered in order to create a comprehensive integrated model of CN structure, function, development, and evolution.

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Smoothened and ARL13B are critical in mouse for superior cerebellar peduncle targeting

Cited by 13 publications

References 99 publications

Loss of ARL13 impedes BBSome-dependent cargo export from Chlamydomonas cilia

Loss of ARL13 impedes BBSome-dependent cargo export from Chlamydomonas cilia

Insights Gained From Zebrafish Models for the Ciliopathy Joubert Syndrome

Cerebellum Lecture: the Cerebellar Nuclei—Core of the Cerebellum

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