title: SOX2 regulates YAP1 to maintain stemness and determine cell fate in the osteo-adipo lineage.
abstract: The osteoblastic and adipocytic lineages arise from mesenchymal stem cells (MSCs), but few regulators of self-renewal and early cell-fate decisions are known. Here, we show that the Hippo pathway effector YAP1 is a direct target of SOX2 and can compensate for the self-renewal defect caused by SOX2 inactivation in osteoprogenitors and MSCs. Osteogenesis is blocked by high SOX2 or YAP1, accelerated by depletion of either one, and the inhibition of osteogenesis by SOX2 requires YAP1. SOX2 favors adipogenesis and induces PPARγ, but adipogenesis can only occur with moderate levels of YAP1. YAP1 induction by SOX2 is restrained in adipogenesis, and both YAP1 overexpression and depletion inhibit the process. YAP1 binds β-catenin and directly induces the Wnt antagonist Dkk1 to dampen pro-osteogenic Wnt signals. We demonstrate a Hippo-independent regulation of YAP1 by SOX2 that cooperatively antagonizes Wnt/β-catenin signals and regulates PPARγ to determine osteogenic or adipocytic fates.
authors.affiliation: National Creative Initiatives Center for Cell Division and Differentiation, Department of Biological Sciences, Korea Advanced Institute of Science and Technology (KAIST), 373-1 Guseoung-D, Yuseong-G, Daejeon 305-701, Korea.
authors.forename: Eunjeong
authors.initials: E
authors.lastname: Seo
authors.forename: Upal
authors.initials: U
authors.lastname: Basu-Roy
authors.forename: Preethi H
authors.initials: PH
authors.lastname: Gunaratne
authors.forename: Cristian
authors.initials: C
authors.lastname: Coarfa
authors.forename: Dae-Sik
authors.initials: DS
authors.lastname: Lim
authors.forename: Claudio
authors.initials: C
authors.lastname: Basilico
authors.forename: Alka
authors.initials: A
authors.lastname: Mansukhani
mesh_terms: D048868:Adaptor Proteins, Signal Transducing / Q000235:genetics / Q000378:metabolism*; D017667:Adipocytes / Q000166:cytology* / Q000378:metabolism; D050156:Adipogenesis; D000818:Animals; D018797:Cell Cycle Proteins; D002454:Cell Differentiation / Q000502:physiology; D048708:Cell Growth Processes / Q000502:physiology; D019070:Cell Lineage; D059630:Mesenchymal Stem Cells / Q000166:cytology* / Q000378:metabolism; D051379:Mice; D008813:Mice, Inbred ICR; D010011:Osteocytes / Q000166:cytology* / Q000378:metabolism; D010012:Osteogenesis; D010750:Phosphoproteins / Q000235:genetics / Q000378:metabolism*; D055748:SOXB1 Transcription Factors / Q000235:genetics / Q000378:metabolism*; D015398:Signal Transduction; D014162:Transfection; D051153:Wnt Proteins / Q000378:metabolism; D060449:Wnt Signaling Pathway; D000091102:YAP-Signaling Proteins; D051176:beta Catenin / Q000378:metabolism
chemical_list: D048868:Adaptor Proteins, Signal Transducing; D018797:Cell Cycle Proteins; D010750:Phosphoproteins; D055748:SOXB1 Transcription Factors; C527783:Sox2 protein, mouse; D051153:Wnt Proteins; D000091102:YAP-Signaling Proteins; C486223:Yap1 protein, mouse; D051176:beta Catenin