斑马鱼<italic style="font-style: italic">cdt1</italic>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; 王勇; 祝岩清; 罗丽健

doi:10.1631/jzus.B2300195

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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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Correspondence | Updated：2024-12-02

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
Loss-of-function of zebrafish cdt1 causes retarded body growth and underdeveloped gonads resembling human Meier-Gorlin syndrome
浙江大学学报（英文版）（B辑：生物医学和生物技术） 2023年24卷第11期页码：1037-1046
Affiliations：

1.MOE Key Laboratory for Molecular Animal Nutrition, College of Animal Sciences, Zhejiang University, Hangzhou 310058, China
2.Pathology Department of Taizhou Hospital, Zhejiang University, Taizhou 317000, China
Funds：
DOI：10.1631/jzus.B2300195
中图分类号：
CSTR：
纸质出版日期： 2023-11-15 ，

收稿日期： 2023-03-21 ，

修回日期： 2023-05-12 ，
Accepted：

何一囡,王勇,祝岩清等.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[J].浙江大学学报（英文版）（B辑：生物医学和生物技术）,2023,24(11):1037-1046.

YINAN HE, YONG WANG, YANQING ZHU, et al. 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 (biomedicine & biotechnology), 2023, 24(11): 1037-1046.
何一囡,王勇,祝岩清等.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[J].浙江大学学报（英文版）（B辑：生物医学和生物技术）,2023,24(11):1037-1046. DOI： 10.1631/jzus.B2300195.

YINAN HE, YONG WANG, YANQING ZHU, et al. 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 (biomedicine & biotechnology), 2023, 24(11): 1037-1046. DOI： 10.1631/jzus.B2300195.

摘要

Abstract

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

斑马鱼N端序列cdt1-201cdt1-202侏儒症不育

Keywords

references

Alfa CE, Booher R, Beach D, et al., 1989. Fission yeast cyclin: subcellular localisation and cell cycle regulation. J Cell Sci, 1989(S12):9-19. https://doi.org/10.1242/jcs.1989.supplement_12.2https://doi.org/10.1242/jcs.1989.supplement_12.2

Bicknell LS, Walker S, Klingseisen A, et al., 2011. Mutations in ORC1, encoding the largest subunit of the origin recognition complex, cause microcephalic primordial dwarfism resembling Meier-Gorlin syndrome. Nat Genet, 43(4):350-355. https://doi.org/10.1038/ng.776https://doi.org/10.1038/ng.776

de Munnik SA, Hoefsloot EH, Roukema J, et al., 2015. Meier-Gorlin syndrome. Orphanet J Rare Dis, 10:114. https://doi.org/10.1186/s13023-015-0322-xhttps://doi.org/10.1186/s13023-015-0322-x

Hofmann JF, Beach D, 1994. cdt1 is an essential target of the Cdc10/Sct1 transcription factor: requirement for DNA replication and inhibition of mitosis. EMBO J, 13‍(2):425-434. https://doi.org/10.1002/j.1460-2075.1994.tb06277.xhttps://doi.org/10.1002/j.1460-2075.1994.tb06277.x

Kanellou A, Giakoumakis NN, Panagopoulos A, et al., 2020. The licensing factor Cdt1 links cell cycle progression to the DNA damage response. Anticancer Res, 40(5):2449-2456. https://doi.org/10.21873/anticanres.14214https://doi.org/10.21873/anticanres.14214

Ma ZP, Zhu PP, Shi H, et al., 2019. PTC-bearing mRNA elicits a genetic compensation response via Upf3a and COMPASS components. Nature, 568(7751):259-263. https://doi.org/10.1038/s41586-019-1057-yhttps://doi.org/10.1038/s41586-019-1057-y

Maiorano D, Moreau J, Méchali M, 2000. XCDT1 is required for the assembly of pre-replicative complexes in Xenopus laevis. Nature, 404(6778):622-625. https://doi.org/10.1038/35007104https://doi.org/10.1038/35007104

Nazarenko MS, Viakhireva IV, Skoblov MY, et al., 2022. Meier-Gorlin syndrome: clinical misdiagnosis, genetic testing and functional analysis of ORC6 mutations and the development of a prenatal test. Int J Mol Sci, 23(16):9234. https://doi.org/10.3390/ijms23169234https://doi.org/10.3390/ijms23169234

Nishitani H, Lygerou Z, Nishimoto T, et al., 2000. The Cdt1 protein is required to license DNA for replication in fission yeast. Nature, 404(6778):625-628. https://doi.org/10.1038/35007110https://doi.org/10.1038/35007110

Pozo PN, Cook JG, 2017. Regulation and function of Cdt1; a key factor in cell proliferation and genome stability. Genes (Basel), 8(1):2. https://doi.org/10.3390/genes8010002https://doi.org/10.3390/genes8010002

Vaziri C, Saxena S, Jeon Y, et al., 2003. A p53-dependent checkpoint pathway prevents rereplication. Mol Cell, 11(4):997-1008. https://doi.org/10.1016/s1097-2765(03)00099-6https://doi.org/10.1016/s1097-2765(03)00099-6

Whittaker AJ, Royzman I, Orr-Weaver TL, 2000. Drosophila Double parked: a conserved, essential replication protein that colocalizes with the origin recognition complex and links DNA replication with mitosis and the down-regulation of S phase transcripts. Genes Dev, 14(14):1765-1776. https://doi.org/10.1101/gad.14.14.1765https://doi.org/10.1101/gad.14.14.1765

Wittkopp N, Huntzinger E, Weiler C, et al., 2009. Nonsense-mediated mRNA decay effectors are essential for zebrafish embryonic development and survival. Mol Cell Biol, 29(13):3517-3528. https://doi.org/10.1128/MCB.00177-09https://doi.org/10.1128/MCB.00177-09

Wohlschlegel JA, Dwyer BT, Dhar SK, et al., 2000. Inhibition of eukaryotic DNA replication by geminin binding to Cdt1. Science, 290(5500):2309-2312. https://doi.org/10.1126/science.290.5500.2309https://doi.org/10.1126/science.290.5500.2309

Yao LK, Chen J, Wu XT, et al., 2017. Zebrafish cdc6 hypomorphic mutation causes Meier-Gorlin syndrome-like phenotype. Hum Mol Genet, 26(21):4168-4180. https://doi.org/10.1093/hmg/ddx305https://doi.org/10.1093/hmg/ddx305

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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

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

DOI：10.1631/jzus.B2300195

摘要

Abstract

关键词

Keywords

references