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.
摘要：
驱动蛋白马达通过控制细胞内运输在发育中起着基本作用，主轴总成,和微管组织。在人类中,携带KIF11突变的患者患有常染色体显性遗传性疾病，称为小头畸形，伴有或不伴有脉络膜视网膜病变，淋巴水肿,或智力低下（MCLMR）。虽然KIF11蛋白的有丝分裂功能已经在中心体分离和纺锤体组装中得到了很好的证明，KIF11功能障碍和MCLMR的细胞机制尚不清楚.在这项研究中,我们建立了KIF11抑制的小鸡和斑马鱼模型，发现KIF11抑制导致小头畸形，脉络膜视网膜病变,和体内严重的发育缺陷。值得注意的是,KIF11的功能丧失导致单极纺锤体和染色体错位的形成，最终导致细胞周期停滞，染色体不稳定,细胞死亡。我们的结果表明，KIF11对于主轴组装至关重要，染色体排列,和祖细胞的细胞周期进程，表明多倍体和MCLMR之间的潜在联系。我们的数据显示KIF11抑制会导致小头畸形，脉络膜视网膜病变,通过单极纺锤体的形成和发育障碍，多倍体,和细胞周期停滞。
