RNA-binding protein SAMD4 regulates skeleton development through translational inhibition of Mig6 expression.
RNA-binding protein SAMD4 regulates skeleton development through translational inhibition of Mig6 expression.
复制标题
RNA结合蛋白SAMD4通过翻译抑制Mig6表达来调节骨骼发育
DOI：
10.1038/celldisc.2016.50
复制
发表时间：
2017
期刊：
影响因子：
33.5
通讯作者：
Zou W
中科院分区：
文献类型：
--
作者：
Niu N;Xiang JF;Yang Q;Wang L;Wei Z;Chen LL;Yang L;Zou W
蛋白质翻译调控在炎症反应、癌症的发生和几种神经退行性疾病的发病机制中起着重要作用。然而，蛋白质翻译的调控在哺乳动物骨骼发育中的作用很少被阐述。在这里，我们报道了RNA结合蛋白不育α基序结构域包含蛋白4(Samd4)的缺失导致了小鼠的多种发育缺陷，包括骨发育延迟和成骨减少。Samd4缺陷的间充质祖细胞表现出成骨细胞分化和功能受损。机制研究表明，Samd4结合Mig6mRNA，抑制MIG6蛋白合成。与此一致的是，Samd4缺陷细胞增加了MIG6蛋白水平，Mig6基因的敲除拯救了Samd4缺陷细胞受损的成骨。此外，Samd4基因缺陷小鼠还表现出软骨细胞缺陷，这与Samd4对MIG6蛋白水平的调节一致。这些发现将Samd4定义为以前未报道的成骨细胞发生和骨发育的关键调节因子，这意味着调节蛋白质翻译是调节骨骼形成的重要机制，控制蛋白质翻译可能在代谢性骨疾病中具有治疗潜力，如骨质疏松症。
Protein translation regulation has essential roles in inflammatory responses, cancer initiation and the pathogenesis of several neurodegenerative disorders. However, the role of the regulation of protein translation in mammalian skeleton development has been rarely elaborated. Here we report that the lack of the RNA-binding protein sterile alpha motif domain containing protein 4 (SAMD4) resulted in multiple developmental defects in mice, including delayed bone development and decreased osteogenesis. Samd4-deficient mesenchymal progenitors exhibit impaired osteoblast differentiation and function. Mechanism study demonstrates that SAMD4 binds the Mig6 mRNA and inhibits MIG6 protein synthesis. Consistent with this, Samd4-deficient cells have increased MIG6 protein level and knockdown of Mig6 rescues the impaired osteogenesis in Samd4-deficient cells. Furthermore, Samd4-deficient mice also display chondrocyte defects, which is consistent with the regulation of MIG6 protein level by SAMD4. These findings define SAMD4 as a previously unreported key regulator of osteoblastogenesis and bone development, implying that regulation of protein translation is an important mechanism governing skeletogenesis and that control of protein translation could have therapeutic potential in metabolic bone diseases, such as osteoporosis.