Cyclin E and Cdk2 Control GLD-1, the Mitosis/Meiosis Decision, and Germline Stem Cells in Caenorhabditis elegans
Cyclin E and Cdk2 Control GLD-1, the Mitosis/Meiosis Decision, and Germline Stem Cells in Caenorhabditis elegans
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DOI：
10.1371/journal.pgen.1001348
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发表时间：
2011-03-01
期刊：
影响因子：
4.5
通讯作者：
Kimble, Judith
中科院分区：
文献类型：
--
作者：
Jeong, Johan;Verheyden, Jamie M.;Kimble, Judith
细胞周期与发育事件的协调对于发育期间组织的生成及其在成人中的维持至关重要。这种协调的缺陷可能会改变细胞命运的平衡，造成毁灭性的临床影响。然而，我们对核心细胞周期调节因子与发育调节因子整合的分子机制的理解仍处于起步阶段。这项工作的重点是在秀丽隐杆线虫种系细胞周期和发育调节因子之间的相互作用。关键的发育调节因子控制生殖系干细胞（GSC）自我更新或开始分化：FBF RNA结合蛋白促进自我更新，而GLD RNA调节蛋白促进减数分裂进入。我们首先发现，许多但不是所有的生殖细胞在RNAi耗尽CYE-1后从有丝分裂细胞周期转换到减数分裂细胞周期（C。elegans cyclin E）或CDK-2（C. elegans Cdk 2）的表达。因此，CYE-1/CDK-2影响有丝分裂/减数分裂平衡。我们接下来发现，在CYE-1或CDK-2耗尽后，GLD-1在GSC中异位表达，并且GLD-1去除可以挽救cye-1/cdk-2缺陷。因此，GLD-1对于CYE-1/CDK-2有丝分裂/减数分裂控制至关重要。事实上，GLD-1似乎是CYE-1/CDK-2的直接底物：GLD-1是一种磷蛋白; CYE-1/CDK-2在体内调节其磷酸化;人细胞周期蛋白E/Cdk 2在体外磷酸化GLD-1。转基因GLD-1（AAA）在三个共有CDK磷酸化位点处具有丙氨酸取代。GLD-1（AAA）在GSC中异位表达，并且GLD-1（AAA）转基因生殖系具有比正常有丝分裂区小的有丝分裂区。这些发现共同构成了CYE 1/CDK-2和GLD-1之间的调节联系。最后，我们发现CYE-1/CDK-2与FBF-1一起工作，至少部分地通过降低GLD-1丰度来维持GSC并阻止它们进入减数分裂。因此，CYE-1/CDK-2成为干细胞维持的关键调节因子。我们认为，细胞周期蛋白E和Cdk-2可能被广泛用于控制发育调节剂。
Coordination of the cell cycle with developmental events is crucial for generation of tissues during development and their maintenance in adults. Defects in that coordination can shift the balance of cell fates with devastating clinical effects. Yet our understanding of the molecular mechanisms integrating core cell cycle regulators with developmental regulators remains in its infancy. This work focuses on the interplay between cell cycle and developmental regulators in the Caenorhabditis elegans germline. Key developmental regulators control germline stem cells (GSCs) to self-renew or begin differentiation: FBF RNA-binding proteins promote self-renewal, while GLD RNA regulatory proteins promote meiotic entry. We first discovered that many but not all germ cells switch from the mitotic into the meiotic cell cycle after RNAi depletion of CYE-1 (C. elegans cyclin E) or CDK-2 (C. elegans Cdk2) in wild-type adults. Therefore, CYE-1/CDK-2 influences the mitosis/meiosis balance. We next found that GLD-1 is expressed ectopically in GSCs after CYE-1 or CDK-2 depletion and that GLD-1 removal can rescue cye-1/cdk-2 defects. Therefore, GLD-1 is crucial for the CYE-1/CDK-2 mitosis/meiosis control. Indeed, GLD-1 appears to be a direct substrate of CYE-1/CDK-2: GLD-1 is a phosphoprotein; CYE-1/CDK-2 regulates its phosphorylation in vivo; and human cyclin E/Cdk2 phosphorylates GLD-1 in vitro. Transgenic GLD-1(AAA) harbors alanine substitutions at three consensus CDK phosphorylation sites. GLD-1(AAA) is expressed ectopically in GSCs, and GLD-1(AAA) transgenic germlines have a smaller than normal mitotic zone. Together these findings forge a regulatory link between CYE1/CDK-2 and GLD-1. Finally, we find that CYE-1/CDK-2 works with FBF-1 to maintain GSCs and prevent their meiotic entry, at least in part, by lowering GLD-1 abundance. Therefore, CYE-1/CDK-2 emerges as a critical regulator of stem cell maintenance. We suggest that cyclin E and Cdk-2 may be used broadly to control developmental regulators.