JZUS - Journal of Zhejiang University SCIENCE

Journal of Zhejiang University SCIENCE B

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Loss-of-function of zebrafish cdt1 causes retarded body growth and underdeveloped gonads resembling human Meier-Gorlin syndrome

Author(s): Yinan HE, Yong WANG, Yanqing ZHU, Li Jan LO
Affiliation(s): MOE Key Laboratory for Molecular Animal Nutrition, College of Animal Sciences, Zhejiang University, Hangzhou 310058, China; more
Corresponding email(s): g0403022@zju.edu.cn
Key Words: Zebrafish; cdt1-201 cdt1-202; Dwarfism; Infertility; Unique N-terminal in bony fish

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Yinan HE, Yong WANG, Yanqing ZHU, Li Jan LO. Loss-of-function of zebrafish cdt1 causes retarded body growth and underdeveloped gonads resembling human Meier-Gorlin syndrome[J]. Journal of Zhejiang University Science B,in press.Frontiers of Information Technology & Electronic Engineering,in press.https://doi.org/10.1631/jzus.B2300195

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%T Loss-of-function of zebrafish cdt1 causes retarded body growth and underdeveloped gonads resembling human Meier-Gorlin syndrome
%A Yinan HE
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%A Yanqing ZHU
%A Li Jan LO
%J Journal of Zhejiang University SCIENCE B
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A1 - Yanqing ZHU
A1 - Li Jan LO
J0 - Journal of Zhejiang University Science B
SP - 1037
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doi="https://doi.org/10.1631/jzus.B2300195"

Abstract
Chinese Summary
Academic Network
Reviewer Comment

Abstract: The cell cycle consists of four distinct phases: G0/G1, S (DNA synthesis), G2, and M (mitosis). The G1 to S transition is typified by an accumulation of 4',?6-diamidino-2-phenylindole (DAPI) signal that indicates the rapid DNA synthesis initiated at special sites on DNA, generally called the Ori (origin of replication) (Alfa et al., 1989). The cell division cycle 10 (Cdc10)?-dependent transcript 1 (Cdt1) is bestowed the term �replication origin licensing factor� for its role in warranting replication once (and only once) per round of the eukaryotic cell cycle, during the S phase (Pozo and Cook, 2017). In a normal cell cycle, Cdt1 is present only in the G1 and S entry phases, whereas Geminin, a protein that targets Cdt1 for S-phase-dependent proteolysis, is present in the S and G2 phases. Failure of this gatekeeping task as observed in cdt1 overexpression, for example in yeast, leads to inappropriate origin firing (also termed re-replication (Vaziri et al., 2003)) and eventually DNA damage checkpoint activation (Kanellou et al., 2020).

斑马鱼cdt1缺失导致类似人类Meier-Gorlin疾病的侏儒症及性腺发育不全综合征

何一囡¹，王勇²，祝岩清¹，罗丽健¹
¹浙江大学动物科学学院，动物分子营养学教育部重点实验室，中国杭州市，310058
²浙江大学台州医院病理科，中国台州市，317000
摘要：染色质许可和DNA复制因子1（Cdt1）是复制起始许可的主要调控因子，也是组成复制前复合物的核心成员。细胞通过依赖Cdt1的波动水平，且在每个周期中通过调节其总量以确保DNA仅复制一次。Cdt1功能缺陷会造成DNA过度复制，最终导致基因组不稳定。虽然酵母中cdt1和人类Meier-Gorlin综合征（MGS）患者中的CDT1已被广泛研究，但缺乏脊椎动物模型。我们发现在硬骨鱼类分支的几个鲤形目物种（包括斑马鱼）中，Cdt1蛋白在其N末端插入一段其他脊椎动物中没有的独特无序序列。通过分析在cdt1基因中携带移码缺失的遗传性斑马鱼突变体（命名为cdt1^zju1），我们发现突变胚胎虽然几乎无任何早期胚胎表型异常，但成年突变斑马鱼却表现出侏儒症、生存能力降低的症状，以及性腺发育不全且不育。此外，我们同样发现除转录本cdt1-201外，斑马鱼还存在第二个cdt1转录本--cdt1-202，它是通过跳过外显子2产生，这在其他生物中暂无报道。有意思的是cdt1-202在cdt1-201纯合突变体中显著上调。上述研究结果表明，cdt1-202转录本可能可以补偿cdt1-201在早期发育过程中的功能损失，但不能补偿后期生长，这可支持斑马鱼作为研究人类MGS的遗传模型。

关键词组：斑马鱼；N端序列；cdt1-201；cdt1-202；侏儒症；不育

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Reference

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[15]YaoLK, ChenJ, WuXT, et al., 2017. Zebrafish cdc6 hypomorphic mutation causes Meier-Gorlin syndrome-like phenotype. Hum Mol Genet, 26(21):4168-4180.

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斑马鱼cdt1缺失导致类似人类Meier-Gorlin疾病的侏儒症及性腺发育不全综合征

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