Hu Jianjun, Lu Jie, Lian Gewei, Ferland Russell J, Dettenhofer Markus, Sheen Volney L
Department of Neurology, Beth Israel Deaconess Medical Center and Harvard Medical School, Boston, MA 02115, USA.
Center for Neuropharmacology and Neuroscience, Albany Medical College, Albany, NY 12208, USA.
Hum Mol Genet. 2014 Sep 1;23(17):4663-73. doi: 10.1093/hmg/ddu186. Epub 2014 Apr 23.
Filamin B (FlnB) is an actin-binding protein thought to transduce signals from various membrane receptors and intracellular proteins onto the actin cytoskeleton. Formin1 (Fmn1) is an actin-nucleating protein, implicated in actin assembly and intracellular signaling. Human mutations in FLNB cause several skeletal disorders associated with dwarfism and early bone fusion. Mouse mutations in Fmn1 cause aberrant fusion of carpal digits. We report here that FlnB and Fmn1 physically interact, are co-expressed in chondrocytes in the growth plate and share overlapping expression in the cell cytoplasm and nucleus. Loss of FlnB leads to a dramatic decrease in Fmn1 expression at the hypertrophic-to-ossification border. Loss of Fmn1-FlnB in mice leads to a more severe reduction in body size, weight and growth plate length, than observed in mice following knockout of either gene alone. Shortening of the long bone is associated with a decrease in chondrocyte proliferation and an overall delay in ossification in the double-knockout mice. In contrast to FlnB null, Fmn1 loss results in a decrease in the width of the prehypertrophic zone. Loss of both proteins, however, causes an overall decrease in the width of the proliferation zone and an increase in the differentiated hypertrophic zone. The current findings suggest that Fmn1 and FlnB have shared and independent functions. FlnB loss promotes prehypertrophic differentiation whereas Fmn1 leads to a delay. Both proteins, however, regulate chondrocyte proliferation, and FlnB may regulate Fmn1 function at the hypertrophic-to-ossification border, thereby explaining the overall delay in ossification.
细丝蛋白B（FlnB）是一种肌动蛋白结合蛋白，被认为可将来自各种膜受体和细胞内蛋白的信号传导至肌动蛋白细胞骨架。formin1（Fmn1）是一种肌动蛋白成核蛋白，与肌动蛋白组装和细胞内信号传导有关。FLNB的人类突变会导致几种与侏儒症和早期骨融合相关的骨骼疾病。Fmn1的小鼠突变会导致腕骨指异常融合。我们在此报告，FlnB和Fmn1发生物理相互作用，在生长板的软骨细胞中共同表达，并在细胞质和细胞核中具有重叠表达。FlnB的缺失导致肥大到骨化边界处Fmn1表达急剧下降。与单独敲除任一基因的小鼠相比，小鼠中Fmn1-FlnB的缺失导致体型、体重和生长板长度的更严重降低。长骨缩短与双敲除小鼠中软骨细胞增殖减少和骨化总体延迟有关。与FlnB缺失不同，Fmn1缺失导致肥大前区宽度减小。然而，两种蛋白的缺失都会导致增殖区宽度总体减小，而分化的肥大区增加。目前的研究结果表明，Fmn1和FlnB具有共同和独立的功能。FlnB缺失促进肥大前分化，而Fmn1导致延迟。然而，两种蛋白都调节软骨细胞增殖，并且FlnB可能在肥大到骨化边界处调节Fmn1功能，从而解释了骨化的总体延迟。
