Nash Family Department of Neuroscience, Friedman Brain Institute, Icahn School of Medicine at Mount Sinai, New York, NY, USA.
Department of Pharmacological Sciences, Icahn School of Medicine at Mount Sinai, New York, NY, USA.
Nat Commun. 2021 Oct 14;12(1):6019. doi: 10.1038/s41467-021-26296-7.
During morphogenesis, molecular mechanisms that orchestrate biomechanical dynamics across cells remain unclear. Here, we show a role of guidance receptor Plexin-B2 in organizing actomyosin network and adhesion complexes during multicellular development of human embryonic stem cells and neuroprogenitor cells. Plexin-B2 manipulations affect actomyosin contractility, leading to changes in cell stiffness and cytoskeletal tension, as well as cell-cell and cell-matrix adhesion. We have delineated the functional domains of Plexin-B2, RAP1/2 effectors, and the signaling association with ERK1/2, calcium activation, and YAP mechanosensor, thus providing a mechanistic link between Plexin-B2-mediated cytoskeletal tension and stem cell physiology. Plexin-B2-deficient stem cells exhibit premature lineage commitment, and a balanced level of Plexin-B2 activity is critical for maintaining cytoarchitectural integrity of the developing neuroepithelium, as modeled in cerebral organoids. Our studies thus establish a significant function of Plexin-B2 in orchestrating cytoskeletal tension and cell-cell/cell-matrix adhesion, therefore solidifying the importance of collective cell mechanics in governing stem cell physiology and tissue morphogenesis.
在形态发生过程中，协调细胞间生物力学动态的分子机制尚不清楚。在这里，我们展示了导向受体 Plexin-B2 在人类胚胎干细胞和神经祖细胞的多细胞发育过程中组织肌动球蛋白网络和黏附复合物中的作用。Plexin-B2 的操作会影响肌动球蛋白的收缩性，导致细胞刚度和细胞骨架张力以及细胞-细胞和细胞-基质黏附的变化。我们已经描绘了 Plexin-B2、RAP1/2 效应器的功能结构域，以及与 ERK1/2、钙激活和 YAP 机械传感器的信号关联，从而为 Plexin-B2 介导的细胞骨架张力与干细胞生理学之间提供了一个机械联系。Plexin-B2 缺失的干细胞表现出过早的谱系分化，而 Plexin-B2 活性的平衡水平对于维持发育中的神经上皮的细胞结构完整性至关重要，这在大脑类器官中得到了模拟。因此，我们的研究确立了 Plexin-B2 在协调细胞骨架张力和细胞-细胞/细胞-基质黏附方面的重要功能，从而巩固了集体细胞力学在调控干细胞生理学和组织形态发生中的重要性。
