Pref-1 regulates mesenchymal cell commitment and differentiation through Sox9.
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.
Wang
Yuhui
Y
Department of Nutritional Science and Toxicology, University of California, Berkeley, Berkeley, CA 94720, USA.
Sul
Hei Sook
HS
D017667:Adipocytes / Q000166:cytology / Q000502:physiology; D000818:Animals; D001854:Bone Marrow Cells / Q000502:physiology; D022762:CCAAT-Enhancer-Binding Proteins / Q000235:genetics / Q000378:metabolism; D002135:Calcium-Binding Proteins; D002454:Cell Differentiation / Q000502:physiology*; D002460:Cell Line; D019070:Cell Lineage; D019902:Chondrocytes / Q000166:cytology / Q000502:physiology; D005347:Fibroblasts / Q000166:cytology / Q000502:physiology; D036341:Intercellular Signaling Peptides and Proteins / Q000235:genetics / Q000378:metabolism*; D016086:Lentivirus / Q000235:genetics / Q000378:metabolism; D059630:Mesenchymal Stem Cells / Q000166:cytology / Q000502:physiology*; D051379:Mice; D018345:Mice, Knockout; D010006:Osteoblasts / Q000166:cytology / Q000502:physiology; D047495:PPAR gamma / Q000235:genetics / Q000378:metabolism; D011401:Promoter Regions, Genetic; D034741:RNA, Small Interfering / Q000235:genetics / Q000378:metabolism; D055758:SOX9 Transcription Factor / Q000235:genetics / Q000378:metabolism*; D017154:Stromal Cells / Q000502:physiology
D022762:CCAAT-Enhancer-Binding Proteins; D002135:Calcium-Binding Proteins; C512925:Dlk1 protein, mouse; D036341:Intercellular Signaling Peptides and Proteins; D047495:PPAR gamma; D034741:RNA, Small Interfering; D055758:SOX9 Transcription Factor; C527933:Sox9 protein, mouse