Tsikolia Nikoloz, Nguyen Dinh Thach Lam, Tee Yee Han
Institute of Anatomy and Cell Biology, University Medical Centre Göttingen, Kreuzbergring 36, 37075, Göttingen, Germany.
Mechanobiology Institute, National University of Singapore, 117411, Singapore.
Curr Opin Cell Biol. 2025 Aug;95:102564. doi: 10.1016/j.ceb.2025.102564. Epub 2025 Jun 21.
Establishment of left-right (LR) asymmetry relies on a multistep interplay of molecular signaling and physical processes. Initial LR symmetry breaking in several model vertebrates was shown to take place at the LR organizer (LRO) where chiral rotation of monocilia produces a leftward fluid flow. Subsequent bending of sensory cilia triggers Pkd2-channel-mediated calcium transients which in turn are required for induction of asymmetrical signaling upstream of morphological asymmetries, emphasizing the role of mechanosensation in flow detection. Crucially, unidirectional flow and its detection were suggested to require cellular-scale asymmetries including planar cell polarity-mediated posterior position and ultrastructural chirality of motile cilia as well as asymmetric Pkd2 localization within sensory cilia. Alternative mechanisms of LR symmetry breaking operate in models like the chick embryo, where asymmetry of gene expression is preceded by leftward primitive node rotation suggesting mechanisms based on cytoskeletal chirality known from invertebrate models including Caenorhabditis elegans and fruit fly. Investigation of chirality at the cellular level suggests that chirality of components of cytoskeleton, particularly actin filaments, is amplified by distinct modules based i.e. on formin-actin and myosin-actin interactions which drive intracellular swirling and cortical flow, providing a basis for LR asymmetry. Cellular chirality can organize LR asymmetry of multicellular behavior as observed in the chiral alignment of fibroblasts. The integration of molecular, cellular, and tissue-scale chirality highlights conserved and divergent mechanisms underpinning LR symmetry breaking across species. Unraveling these processes may illuminate pathways connecting cytoskeletal dynamics to organismal asymmetry, offering insights into development and evolution.
左右（LR）不对称性的建立依赖于分子信号传导和物理过程的多步骤相互作用。在几种模式脊椎动物中，最初的LR对称性破缺发生在LR组织者（LRO）处，单纤毛的手性旋转产生向左的流体流动。随后感觉纤毛的弯曲触发了Pkd2通道介导的钙瞬变，而钙瞬变反过来又是形态不对称上游不对称信号诱导所必需的，这强调了机械感觉在流体检测中的作用。至关重要的是，单向流动及其检测被认为需要细胞尺度的不对称性，包括平面细胞极性介导的后部位置、运动纤毛的超微结构手性以及感觉纤毛内Pkd2的不对称定位。LR对称性破缺的替代机制在鸡胚等模型中起作用，在鸡胚中，基因表达的不对称性之前是原始节点向左旋转，这表明其机制基于从包括秀丽隐杆线虫和果蝇在内的无脊椎动物模型中已知的细胞骨架手性。在细胞水平上对手性的研究表明，细胞骨架成分，特别是肌动蛋白丝的手性，通过基于例如formin-肌动蛋白和肌球蛋白-肌动蛋白相互作用的不同模块而被放大，这些相互作用驱动细胞内涡旋和皮层流动，为LR不对称性提供了基础。细胞手性可以组织多细胞行为的LR不对称性，如在成纤维细胞的手性排列中观察到的那样。分子、细胞和组织尺度手性的整合突出了跨物种LR对称性破缺的保守和不同机制。揭示这些过程可能会阐明连接细胞骨架动力学与机体不对称性的途径，为发育和进化提供见解。
