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dc.contributor.authorCsukasi, Fabiana
dc.date.accessioned2022-11-25T11:56:01Z
dc.date.available2022-11-25T11:56:01Z
dc.date.issued2022
dc.identifier.urihttps://hdl.handle.net/10630/25494
dc.description.abstractAlterations in the balance between skeletogenesis and adipogenesis is a pathogenic feature in multiple skeletal disorders. Clinically, enhanced bone marrow adiposity in bones impairs mobility and increases fracture risk, reducing the quality of life of patients. The molecular mechanism that underlies the balance between skeletogenesis and adipogenesis is not completely understood but alterations in skeletal progenitor cells’ differentiation pathway plays a key role. We recently demonstrated that parathyroid hormone (PTH)/PTH-related peptide (PTHrP) control the levels of DEPTOR, an inhibitor of the mechanistic target of rapamycin (mTOR), and that DEPTOR levels are altered in different skeletal diseases. Here, we show that mutations in the PTH receptor-1 (PTH1R) alter the differentiation of skeletal progenitors in two different skeletal genetic disorders and lead to accumulation of fat or cartilage in bones. Mechanistically, DEPTOR controls the subcellular localization of TAZ (transcriptional co-activator with a PDZ-binding domain), a transcriptional regulator that governs skeletal stem cells differentiation into either bone and fat. We show that DEPTOR regulation of TAZ localization is achieved through the control of Dishevelled2 (DVL2) phosphorylation and that it ultimately translates into the transcriptional control of PTH and WNT target genes. Depending on nutrient availability, DEPTOR directly interacts with PTH1R to regulate PTH/PTHrP signaling or it forms a complex with TAZ, to prevent its translocation to the nucleus and therefore inhibit its transcriptional activity. Our data point DEPTOR as a key molecule in skeletal progenitor differentiation; its dysregulation under pathologic conditions results in aberrant bone/fat balance.es_ES
dc.description.sponsorshipUniversidad de Málaga. Campus de Excelencia Internacional Andalucía Tech.es_ES
dc.language.isoenges_ES
dc.rightsinfo:eu-repo/semantics/openAccesses_ES
dc.subjectOsteogénesises_ES
dc.subjectEsqueleto humano - Alteracioneses_ES
dc.subject.otherDEPTORes_ES
dc.subject.otherSkeletal diseaseses_ES
dc.subject.otherTAZes_ES
dc.subject.otherOsteogenesises_ES
dc.subject.otherAdipogenesises_ES
dc.titleSkeletal diseases caused by mutations in PTH1R show aberrant differentiation of skeletal progenitors due to dysregulation of DEPTORes_ES
dc.typeinfo:eu-repo/semantics/conferenceObjectes_ES
dc.centroFacultad de Cienciases_ES
dc.relation.eventtitle4th H Fleisch Workshopes_ES
dc.relation.eventplaceBrujas, Bélgicaes_ES
dc.relation.eventdate20/11/2022es_ES


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