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  2. Loss-of-function of kinesin-5 KIF11 causes microcephaly, chorioretinopathy, and developmental disorders through chromosome instability and cell cycle arrest

Loss-of-function of kinesin-5 KIF11 causes microcephaly, chorioretinopathy, and developmental disorders through chromosome instability and cell cycle arrest

  • Exp Cell Res. 2024 Feb 15:113975. doi: 10.1016/j.yexcr.2024.113975.
Yi Zhou 1 Meng-Fei Xu 1 Jie Chen 1 Jing-Lian Zhang 1 Xin-Yao Wang 1 Min-Hui Huang 1 Ya-Lan Wei 2 Zhen-Yu She 3
Affiliations

Affiliations

  • 1 Department of Cell Biology and Genetics, The School of Basic Medical Sciences, Fujian Medical University, Fuzhou, Fujian, 350122, China; Key Laboratory of Stem Cell Engineering and Regenerative Medicine, Fujian Province University, Fuzhou, Fujian, 350122, China.
  • 2 Medical Research Center, Fujian Maternity and Child Health Hospital, Fuzhou, Fujian, 350001, China; College of Clinical Medicine for Obstetrics & Gynecology and Pediatrics, Fujian Medical University, Fuzhou, Fujian, 350122, China.
  • 3 Department of Cell Biology and Genetics, The School of Basic Medical Sciences, Fujian Medical University, Fuzhou, Fujian, 350122, China; Key Laboratory of Stem Cell Engineering and Regenerative Medicine, Fujian Province University, Fuzhou, Fujian, 350122, China. Electronic address: zhenyushe@fjmu.edu.cn.
Abstract

Kinesin motors play a fundamental role in development by controlling intracellular transport, spindle assembly, and microtubule organization. In humans, patients carrying mutations in KIF11 suffer from an autosomal dominant inheritable disease called microcephaly with or without chorioretinopathy, lymphoedema, or mental retardation (MCLMR). While mitotic functions of KIF11 proteins have been well documented in centrosome separation and spindle assembly, cellular mechanisms underlying KIF11 dysfunction and MCLMR remain unclear. In this study, we generate KIF11-inhibition chick and zebrafish models and find that KIF11 inhibition results in microcephaly, chorioretinopathy, and severe developmental defects in vivo. Notably, loss-of-function of KIF11 causes the formation of monopolar spindle and chromosome misalignment, which finally contribute to cell cycle arrest, chromosome instability, and cell death. Our results demonstrate that KIF11 is crucial for spindle assembly, chromosome alignment, and cell cycle progression of progenitor stem cells, indicating a potential link between polyploidy and MCLMR. Our data have revealed that KIF11 inhibition cause microcephaly, chorioretinopathy, and development disorders through the formation of monopolar spindle, polyploid, and cell cycle arrest.

Keywords

Chorioretinopathy; Chromosome instability; KIF11; Kinesin; MCLMR; Microcephaly.

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