Chemokine signaling links cell-cycle progression and cilia formation for left-right symmetry breaking
Chemokine signaling links cell-cycle progression and cilia formation for left-right symmetry breaking
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趋化因子信号传导将细胞周期进程和纤毛形成联系起来，导致左右对称性破坏
DOI：
10.1371/journal.pbio.3000203
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发表时间：
2019-08-01
期刊：
影响因子：
9.8
通讯作者：
Wang, Qiang
中科院分区：
文献类型：
--
作者：
Liu, Jingwen;Zhu, Chengke;Wang, Qiang
斑马鱼背侧前体细胞（DFC）在外延期间经历剧烈增殖，然后退出细胞周期以产生库普弗囊泡（KV），这是建立左右（L-R）不对称性所必需的纤毛器官。DFC增殖缺陷往往伴随着受损的纤毛伸长KV，但细胞周期进程和纤毛形成之间的功能和分子相互作用仍然未知。在这里，我们表明，趋化因子受体Cxcr 4a是所需的L-R偏侧控制DFC增殖和KV纤毛发生。功能分析显示，Cxcr 4a通过细胞外调节的MAP激酶（ERK）1/2信号刺激细胞周期蛋白D1的表达，加速DFCs的G1/S转换，并稳定活动纤毛的主要调节因子叉头盒j1 a（Foxj 1a）。从机制上讲，细胞周期蛋白D1-细胞周期蛋白依赖性激酶（CDK）4/6驱动DFC增殖期间的G1/S转换，并磷酸化Foxj 1a，从而破坏其与蛋白酶体26 S亚基，非ATP酶4 b（Psmd 4 b），19 S调节亚基的关联。这阻止了Foxj 1a的泛素（Ub）非依赖性蛋白酶体降解。我们的研究揭示了Cxcr 4信号在L-R模式中的作用，并为细胞周期进程和纤毛发生之间的分子联系提供了基本的见解。
Zebrafish dorsal forerunner cells (DFCs) undergo vigorous proliferation during epiboly and then exit the cell cycle to generate Kupffer's vesicle (KV), a ciliated organ necessary for establishing left-right (L-R) asymmetry. DFC proliferation defects are often accompanied by impaired cilia elongation in KV, but the functional and molecular interaction between cell-cycle progression and cilia formation remains unknown. Here, we show that chemokine receptor Cxcr4a is required for L-R laterality by controlling DFC proliferation and KV ciliogenesis. Functional analysis revealed that Cxcr4a accelerates G1/S transition in DFCs and stabilizes forkhead box j1a (Foxj1a), a master regulator of motile cilia, by stimulating Cyclin D1 expression through extracellular regulated MAP kinase (ERK) 1/2 signaling. Mechanistically, Cyclin D1-cyclin-dependent kinase (CDK) 4/6 drives G1/S transition during DFC proliferation and phosphorylates Foxj1a, thereby disrupting its association with proteasome 26S subunit, non-ATPase 4b (Psmd4b), a 19S regulatory subunit. This prevents the ubiquitin (Ub)-independent proteasomal degradation of Foxj1a. Our study uncovers a role for Cxcr4 signaling in L-R patterning and provides fundamental insights into the molecular linkage between cell-cycle progression and ciliogenesis.