Pref-1通过Sox9调节间充质细胞的定向分化。
Pref-1 regulates mesenchymal cell commitment and differentiation through Sox9.
作者信息
Wang Yuhui, Sul Hei Sook
机构信息
Department of Nutritional Science and Toxicology, University of California, Berkeley, Berkeley, CA 94720, USA.
出版信息
Cell Metab. 2009 Mar;9(3):287-302. doi: 10.1016/j.cmet.2009.01.013.
Pref-1 is an EGF repeat-containing transmembrane protein that produces a biologically active soluble form by TACE-mediated cleavage. Although Pref-1 inhibition of adipogenesis has been well established, the specific target(s) of Pref-1 or the Pref-1 function in mesenchymal cell commitment/differentiation are not known. Here, we show that Sox9 downregulation is required for adipocyte differentiation and that Pref-1 inhibits adipocyte differentiation through upregulating Sox9 expression. Sox9 directly binds to the promoter regions of C/EBPbeta and C/EBPdelta to suppress their promoter activity, preventing adipocyte differentiation. Furthermore, we also show that, by inducing Sox9, Pref-1 promotes chondrogenic induction of mesenchymal cells but prevents chondrocyte maturation as well as osteoblast differentiation, with supporting in vivo evidence in Pref-1 null and Pref-1 transgenic mice. Thus, Sox9 is a Pref-1 target, and Pref-1 directs multipotent mesenchymal cells to the chondrogenic lineage but inhibits differentiation into adipocytes as well as osteoblasts and chondrocytes.
Pref-1是一种含有表皮生长因子（EGF）重复序列的跨膜蛋白，可通过肿瘤坏死因子α转换酶（TACE）介导的切割产生具有生物活性的可溶性形式。尽管Pref-1对脂肪生成的抑制作用已得到充分证实，但Pref-1的具体靶点或Pref-1在间充质细胞定向分化中的功能尚不清楚。在此，我们表明脂肪细胞分化需要下调Sox9，且Pref-1通过上调Sox9表达来抑制脂肪细胞分化。Sox9直接结合C/EBPβ和C/EBPδ的启动子区域以抑制其启动子活性，从而阻止脂肪细胞分化。此外，我们还表明，Pref-1通过诱导Sox9促进间充质细胞向软骨细胞的诱导，但阻止软骨细胞成熟以及成骨细胞分化，这在Pref-1基因敲除和Pref-1转基因小鼠中得到了体内证据的支持。因此，Sox9是Pref-1的靶点，且Pref-1引导多能间充质细胞向软骨细胞谱系分化，但抑制其向脂肪细胞以及成骨细胞和软骨细胞的分化。
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