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首页> 外文期刊>Journal of tissue engineering and regenerative medicine >Four and a half domain 2 (FHL2) scaffolding protein is a marker of connective tissues of developing digits and regulates fibrogenic differentiation of limb mesodermal progenitors
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Four and a half domain 2 (FHL2) scaffolding protein is a marker of connective tissues of developing digits and regulates fibrogenic differentiation of limb mesodermal progenitors

机译：四个半导域2（FHL2）支架蛋白是开发数字的结缔组织的标志物，并调节肢体中胚层祖细胞的纤维化分化

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摘要

Four and a half LIM domain 2 (FHL2) is a multifunctional scaffolding protein of well-known function regulating cell signalling cascades and gene transcription in cancer tissues. However, its function in embryonic systems is poorly characterized. Here, we show that Fhl2 is involved in the differentiation of connective tissues of developing limb autopod. We show that Fhl2 exhibits spatially restricted and temporally dynamic expression around the tendons of developing digits, interphalangeal joint capsules, and fibrous peridigital tissue. Immunolabelling analysis of the skeletal progenitors identified a predominant, but not exclusive, cytoplasmic distribution of FHL2 being associated with focal adhesions and actin cytoskeleton. In the course of chondrogenic differentiation of cultures of limb skeletal progenitors, the expression of Fhl2 is down-regulated. Furthermore, cultures of skeletal progenitors overexpressing Fhl2 take on a predominant fibrogenic appearance. Both gain-of-function and loss-of-function experiments in the micromass culture assays revealed a positive transcriptional influence of Fhl2 in the expression of fibrogenic markers including Scleraxis, Tenomodulin, Tenascin C, beta ig-h3, and Tgif1. We further show that the expression of Fhl2 is positively regulated by profibrogenic signals including Tgf beta 2, all-transretinoic acid, and canonical Wnt signalling molecules and negatively regulated by prochondrogenic factors of the bone morphogenetic protein family. Expression of Fhl2 is also regulated negatively in immobilized limbs, but this influence appears to be mediated by other connective tissue markers, such as Tgf beta s and Scleraxis.
机译：四个半肢体结构域2（FHL2）是众所周知的功能调节细胞信号传导级联和癌组织基因转录的多功能支架蛋白。然而，其在胚胎系统中的功能表征不佳。在这里，我们表明FHL2参与了发展肢体AutoPod的结缔组织的分化。我们表明FHL2围绕开发数字，间骨膜关节胶囊和纤维状胬肉组织的肌腱呈现空间限制和时间动态表达。骨骼祖细胞的免疫标记分析鉴定了与局部粘连和肌动蛋白细胞骨架相关的FHL2的主要，但不是排他性的细胞质分布。在肢体骨骼祖细胞培养物的软骨间分化过程中，FHL2的表达被下调。此外，过表达FHL2过表达FHL2的骨骼祖细胞的培养物占据主要纤维原外观。微培养测定中的功能性和功能丧失实验均显示FHL2在纤维原标记表达中的阳性转录影响，包括辛脲，替汀蛋白，腺苷C，βIg-H3和TGIF1。我们进一步表明，FHL2的表达通过包括TGFβ2，全转基金酸和规范WNT信号传导分子的繁殖信号阳性调节，并通过骨形态发生蛋白家族的促进因子负调节。 FHL2的表达也在固定的四肢中负面调节，但这种影响似乎是由其他结缔组织标记的介导的，例如TGFβS和Scleraxis。

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