The Joubert Syndrome Gene arl13b is Critical for Early Cerebellar Development in Zebrafish
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ORIGINAL ARTICLE
The Joubert Syndrome Gene arl13b is Critical for Early Cerebellar Development in Zebrafish Jian Zhu1,2,5 • Han-Tsing Wang1,2 • Yu-Rong Chen1,2 • Ling-Ya Yan1,2 Ying-Ying Han1,2 • Ling-Yan Liu1,2,3 • Ying Cao4 • Zhi-Zhi Liu1,2,3 • Hong A. Xu1,2,3
•
Received: 16 October 2019 / Accepted: 5 March 2020 Ó The Author(s) 2020
Abstract Joubert syndrome is characterized by unique malformation of the cerebellar vermis. More than thirty Joubert syndrome genes have been identified, including ARL13B. However, its role in cerebellar development remains unexplored. We found that knockdown or knockout of arl13b impaired balance and locomotion in zebrafish larvae. Granule cells were selectively reduced in the corpus cerebelli, a structure homologous to the mammalian vermis. Purkinje cell progenitors were also selectively disturbed dorsomedially. The expression of atoh1 and ptf1, proneural genes of granule and Purkinje cells, respectively, were selectively down-regulated along the dorsal midline of the cerebellum. Moreover, wnt1, which is transiently expressed early in cerebellar development, was selectively
Jian Zhu and Han-Tsing Wang have contributed equally to this work.
Electronic supplementary material The online version of this article (https://doi.org/10.1007/s12264-020-00554-y) contains supplementary material, which is available to authorized users. & Hong A. Xu [email protected] 1
Institute of Life Science, Nanchang University, Nanchang 330031, China
2
School of Life Sciences, Nanchang University, Nanchang 330031, China
3
Jiangxi Provincial Collaborative Innovation Center for Cardiovascular, Digestive and Neuropsychiatric Diseases, Nanchang 330031, China
4
Department of Molecular and Cell Biology, Tongji University School of Life Sciences and Technology, Shanghai 200092, China
5
Precise Genome Engineering Center, School of Life Sciences, Guangzhou University, Guangzhou 510006, China
reduced. Intriguingly, activating Wnt signaling partially rescued the granule cell defects in arl13b mutants. These findings suggested that Arl13b is necessary for the early development of cerebellar granule and Purkinje cells. The arl13b-deficient zebrafish can serve as a model organism for studying Joubert syndrome. Keywords Joubert syndrome arl13b Cerebellum Development Granule cell Purkinje cell Wnt
Introduction Joubert syndrome (JS) is an autosomal-recessive neurodevelopmental disorder, which is characterized morphologically by the unique molar tooth sign, a complex malformation of the cerebellar vermis and brainstem, with abnormalities of axonal decussation affecting the corticospinal tract and superior cerebellar peduncles [1]. JS is clinically characterized by impaired motor functions and intellectual disability. Most cases of JS are variably associated with impairments of additional organs, including the retina, kidney, skeleton, and liver. More than 30 genes have been identified to cause JS (213300, Online Mendelian Inheritance in Man). Most of the pro
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