Aix Marseille Université, CNRS, IBDM, 13284 Marseille Cedex 07, France
Institut de Biologie du Développement de Marseille-UMR CNRS 7288, Campus de Luminy-Case 907, 13288 Marseille Cedex 9, France.
J Cell Sci. 2018 Apr 13;131(8):jcs213959. doi: 10.1242/jcs.213959.
During development, cycles of spatiotemporal remodeling of higher-order networks of actin filaments contribute to control cell fate specification and differentiation. Programs for controlling these dynamics are hard-wired into actin-regulatory proteins. The filamin family of actin-binding proteins exert crucial mechanotransduction and signaling functions in tissue morphogenesis. Filamin-B (FLNB) is a key player in chondrocyte progenitor differentiation for endochondral ossification. Biallelic loss-of-function mutations or gain-of-function mutations in cause two groups of skeletal disorders that can be attributed to either the loss of repressive function on TGF-β signaling or a disruption in mechanosensory properties, respectively. In this Review, we highlight a unique family of vertebrate-specific short-lived filamin-binding proteins, the refilins (refilin-A and refilin-B), that modulate filamin-dependent actin crosslinking properties. Refilins are downstream TGF-β effectors in epithelial cells. Double knockout of both refilin-A and refilin-B in mice results in precocious ossification of some axial skeletal elements, leading to malformations that are similar to those seen in -deficient mice. Based on these findings, we present a model summarizing the role of refilins in regulating the mechanosensory functions of FLNB during skeletal development. We also discuss the possible contribution of refilins to FLNB-related skeletal pathologies that are associated with gain-of-function mutations.
在发育过程中，细胞命运特化和分化的肌动蛋白丝高级网络的时空重塑循环有助于控制细胞命运特化和分化。控制这些动力学的程序被硬性编入肌动蛋白调节蛋白中。肌动蛋白结合蛋白的细丝蛋白家族在组织形态发生中发挥着至关重要的机械转导和信号功能。细丝蛋白-B（FLNB）是软骨细胞祖细胞分化为软骨内骨化的关键因子。在 中，双等位基因的功能丧失或功能获得突变分别导致两组骨骼疾病，这可归因于 TGF-β 信号的抑制功能丧失或机械感觉特性的破坏。在这篇综述中，我们强调了一个独特的脊椎动物特异性短寿命细丝蛋白结合蛋白家族，即 refilins（refilin-A 和 refilin-B），它们调节依赖肌动蛋白交联的细丝蛋白特性。Refilins 是上皮细胞中 TGF-β 的下游效应物。在小鼠中同时敲除 refilin-A 和 refilin-B 会导致一些轴性骨骼元素过早骨化，导致类似于 -缺陷小鼠的畸形。基于这些发现，我们提出了一个模型，总结了 refilins 在调节骨骼发育过程中 FLNB 的机械感觉功能中的作用。我们还讨论了 refilins 对与功能获得性突变相关的 FLNB 相关骨骼病理学的可能贡献。
