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Mammalian CDC14 phosphatases control exit from stemness in pluripotent cells
The EMBO Journal ( IF 9.4 ) Pub Date : 2022-11-03 , DOI: 10.15252/embj.2022111251
Carolina Villarroya-Beltri 1 , Ana Filipa B Martins 1 , Alejandro García 1 , Daniel Giménez 2 , Eduardo Zarzuela 3 , Mónica Novo 1 , Cristina Del Álamo 1 , José González-Martínez 1 , Gloria C Bonel-Pérez 1 , Irene Díaz 1 , María Guillamot 1 , Massimo Chiesa 1 , Ana Losada 2 , Osvaldo Graña-Castro 4 , Meritxell Rovira 5, 6 , Javier Muñoz 3 , María Salazar-Roa 1 , Marcos Malumbres 1
Affiliation  

Maintenance of stemness is tightly linked to cell cycle regulation through protein phosphorylation by cyclin-dependent kinases (CDKs). However, how this process is reversed during differentiation is unknown. We report here that exit from stemness and differentiation of pluripotent cells along the neural lineage are controlled by CDC14, a CDK-counteracting phosphatase whose function in mammals remains obscure. Lack of the two CDC14 family members, CDC14A and CDC14B, results in deficient development of the neural system in the mouse and impairs neural differentiation from embryonic stem cells (ESCs). Mechanistically, CDC14 directly dephosphorylates specific proline-directed Ser/Thr residues of undifferentiated embryonic transcription Factor 1 (UTF1) during the exit from stemness, triggering its proteasome-dependent degradation. Multiomic single-cell analysis of transcription and chromatin accessibility in differentiating ESCs suggests that increased UTF1 levels in the absence of CDC14 prevent the proper firing of bivalent promoters required for differentiation. CDC14 phosphatases are dispensable for mitotic exit, suggesting that CDC14 phosphatases have evolved to control stemness rather than cell cycle exit and establish the CDK-CDC14 axis as a critical molecular switch for linking cell cycle regulation and self-renewal.

中文翻译:

哺乳动物 CDC14 磷酸酶控制多能细胞干性的退出

干性的维持与细胞周期通过细胞周期蛋白依赖性激酶 (CDK) 磷酸化的调节密切相关。然而,这个过程在分化过程中如何逆转尚不清楚。我们在此报告,沿神经谱系的多能细胞的干细胞退出和分化是由 CDC14 控制的,CDC14 是一种对抗 CDK 的磷酸酶,其在哺乳动物中的功能仍不清楚。CDC14 家族的两个成员 CDC14A 和 CDC14B 的缺失会导致小鼠神经系统发育缺陷,并损害胚胎干细胞 (ESC) 的神经分化。从机制上讲,CDC14 在退出干性过程中直接使未分化胚胎转录因子 1 (UTF1) 的特定脯氨酸导向的 Ser/Thr 残基去磷酸化,触发其蛋白酶体依赖性降解。对分化 ESC 中转录和染色质可及性的多组学单细胞分析表明,在 CDC14 缺失的情况下,UTF1 水平升高会阻止分化所需的二价启动子的正确启动。CDC14 磷酸酶对于有丝分裂退出是可有可无的,这表明 CDC14 磷酸酶已经进化到控制干性而不是细胞周期退出,并将 CDK-CDC14 轴建立为连接细胞周期调节和自我更新的关键分子开关。
更新日期:2022-11-03
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