Sailer Anne, Anneken Alexander, Li Younan, Lee Sam, Munro Edwin
Department of Molecular Genetics and Cell Biology, University of Chicago, Chicago, IL 60637, USA.
Department of Molecular Genetics and Cell Biology, University of Chicago, Chicago, IL 60637, USA; Committee on Development, Regeneration and Stem Cell Biology, University of Chicago, Chicago, IL 60637, USA.
Dev Cell. 2015 Oct 12;35(1):131-42. doi: 10.1016/j.devcel.2015.09.006.
Dynamic maintenance of cell polarity is essential for development and physiology. Here we combine experiments and modeling to elucidate mechanisms that maintain cortical polarity in the C. elegans zygote. We show that polarity is dynamically stabilized by two coupled cross-inhibitory feedback loops: one involves the oligomeric scaffold PAR-3 and the kinase PAR-1, and the other involves CDC-42 and its putative GAP CHIN-1. PAR-3 and CDC-42 are both required locally to recruit PAR-6/PKC-3, which inhibits PAR-1 (shown previously) and inhibits local growth/accumulation of CHIN-1 clusters. Conversely, PAR-1 inhibits local accumulation of PAR-3 oligomers, while CHIN-1 inhibits CDC-42 (shown previously), such that either PAR-1 or CHIN-1 can prevent recruitment of PAR-6/PKC-3, but loss of both causes complete loss of polarity. Ultrasensitive dependence of CHIN-1 cluster growth on PAR-6/PKC-3 endows this core circuit with bistable dynamics, while transport of CHIN-1 clusters by cortical flow can stabilize the AP boundary against diffusive spread of PAR-6/PKC-3.
细胞极性的动态维持对于发育和生理功能至关重要。在这里，我们结合实验和建模来阐明秀丽隐杆线虫受精卵中维持皮质极性的机制。我们发现，极性由两个耦合的交叉抑制反馈回路动态稳定：一个涉及寡聚支架蛋白PAR-3和激酶PAR-1，另一个涉及CDC-42及其假定的GAP蛋白CHIN-1。PAR-3和CDC-42在局部都是招募PAR-6/PKC-3所必需的，PAR-6/PKC-3可抑制PAR-1（先前已证明）并抑制CHIN-1簇的局部生长/积累。相反，PAR-1抑制PAR-3寡聚体的局部积累，而CHIN-1抑制CDC-42（先前已证明），因此PAR-1或CHIN-1均可阻止PAR-6/PKC-3的招募，但两者均缺失会导致极性完全丧失。CHIN-1簇生长对PAR-6/PKC-3的超敏感依赖性赋予了这个核心回路双稳态动力学，而皮质流对CHIN-1簇的运输可稳定前后轴边界，防止PAR-6/PKC-3的扩散传播。
