美国加州大学旧金山分校Jeremy F. Reiter等研究人员合作发现，一个另类的细胞周期协调多纤毛细胞分化。2024年5月29日，《自然》杂志在线发表了这一最新研究成果。

研究人员展示了分化中的多纤毛细胞将细胞周期调节因子整合到一个新的替代细胞周期中，被称之为多纤毛周期。多纤毛周期重新调配了许多典型的细胞周期调节因子，包括细胞周期蛋白依赖性激酶（CDK）及其同源的细胞周期蛋白。例如，细胞周期蛋白 D1、CDK4 和 CDK6 是有丝分裂 G1 到 S 过程的调节因子，它们是启动多纤毛细胞分化所需的。多纤毛周期扩大了典型细胞周期的某些方面，如中心粒合成，并阻断了其他方面，如DNA复制。

E2F7是典型的S-G2进展的转录调节因子，在多纤毛周期中高水平表达。在多凋亡周期中，E2F7 直接抑制编码 DNA 复制机器的基因表达，并终止类似 S 期的基因表达程序。E2F7的缺失会导致多纤毛细胞DNA合成的异常获得和多纤毛周期进展的失调，从而破坏中心粒的成熟和纤毛的生成。研究人员认为，多纤毛细胞使用一种另类的细胞周期来协调分化，而不是控制增殖。

研究人员表示，典型的有丝分裂细胞周期协调 DNA 复制、中心粒复制和细胞分裂，从一个细胞生成两个细胞。有些细胞，如哺乳动物滋养层巨细胞，利用细胞周期变体（如核内周期）绕过有丝分裂。在哺乳动物呼吸道、脑室和生殖道中发现的分化多纤毛细胞是有丝分裂后的细胞，但会产生数百个中心粒，每个中心粒都会成熟为基底体，并核化出运动的纤毛。一些细胞周期调节因子与多纤毛细胞分化的特定步骤有关。

附：英文原文

Title: An alternative cell cycle coordinates multiciliated cell differentiation

Author: Choksi, Semil P., Byrnes, Lauren E., Konjikusic, Mia J., Tsai, Benedict W. H., Deleon, Rachel, Lu, Quanlong, Westlake, Christopher J., Reiter, Jeremy F.

Issue&Volume: 2024-05-29

Abstract: The canonical mitotic cell cycle coordinates DNA replication, centriole duplication and cytokinesis to generate two cells from one1. Some cells, such as mammalian trophoblast giant cells, use cell cycle variants like the endocycle to bypass mitosis2. Differentiating multiciliated cells, found in the mammalian airway, brain ventricles and reproductive tract, are post-mitotic but generate hundreds of centrioles, each of which matures into a basal body and nucleates a motile cilium3,4. Several cell cycle regulators have previously been implicated in specific steps of multiciliated cell differentiation5,6. Here we show that differentiating multiciliated cells integrate cell cycle regulators into a new alternative cell cycle, which we refer to as the multiciliation cycle. The multiciliation cycle redeploys many canonical cell cycle regulators, including cyclin-dependent kinases (CDKs) and their cognate cyclins. For example, cyclin D1, CDK4 and CDK6, which are regulators of mitotic G1-to-S progression, are required to initiate multiciliated cell differentiation. The multiciliation cycle amplifies some aspects of the canonical cell cycle, such as centriole synthesis, and blocks others, such as DNA replication. E2F7, a transcriptional regulator of canonical S-to-G2 progression, is expressed at high levels during the multiciliation cycle. In the multiciliation cycle, E2F7 directly dampens the expression of genes encoding DNA replication machinery and terminates the Sphase-like gene expression program. Loss of E2F7 causes aberrant acquisition of DNA synthesis in multiciliated cells and dysregulation of multiciliation cycle progression, which disrupts centriole maturation and ciliogenesis. We conclude that multiciliated cells use an alternative cell cycle that orchestrates differentiation instead of controlling proliferation.

DOI: 10.1038/s41586-024-07476-z

Source: https://www.nature.com/articles/s41586-024-07476-z