Analysis of cilia dysfunction phenotypes in zebrafish embryos depleted of Origin recognition complex factors

Maerz, Lars D, Casar Tena, Teresa, Gerhards, Julian, Donow, Cornelia, Jeggo, Penelope A and Philipp, Melanie (2019) Analysis of cilia dysfunction phenotypes in zebrafish embryos depleted of Origin recognition complex factors. European Journal of Human Genetics. ISSN 1018-4813

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Meier–Gorlin syndrome (MGS) is a rare, congenital primordial microcephalic dwarfism disorder. MGS is caused by genetic variants of components of the origin recognition complex (ORC) consisting of ORC1–6 and the pre-replication complex, which together enable origin firing and hence genome replication. In addition, ORC1 has previously been shown to play a role in ciliogenesis. Here, we extend this work and investigate the function of ORC1 and two other members of the complex on cilia at an organismal level. Knockdown experiments in zebrafish confirmed the impact of ORC1 on cilia. ORC1-deficiency confers defects anticipated to arise from impaired cilia function such as formation of oedema, kidney cysts, curved bodies and left–right asymmetry defects. We found ORC1 furthermore required for cilium formation in zebrafish and demonstrate that ciliopathy phenotypes in ORC1-depleted zebrafish could not be rescued by reconstitution with ORC1 bearing a genetic variant previously identified in MGS patients. Loss-of-function of Orc4 and Orc6, respectively, conferred similar ciliopathy phenotypes and cilium shortening in zebrafish, suggesting that several, if not all, components of the ORC regulate ciliogenesis downstream to or in addition to their canonical function in replication initiation. This study presents the first in vivo evidence of an influence of the MGS genes of the ORC family on cilia, and consolidates the possibility that cilia dysfunction could contribute to the clinical manifestation of ORC-deficient MGS.

Item Type: Article
Keywords: Meier-Gorlin Syndrome; ORC1; ORC4; ORC6; cilia biology; left-right symmetry; ciliopathy
Schools and Departments: School of Life Sciences > Sussex Centre for Genome Damage and Stability
Research Centres and Groups: Genome Damage and Stability Centre
Depositing User: Penny Jeggo
Date Deposited: 01 Mar 2019 14:55
Last Modified: 01 Mar 2019 14:55

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