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Reciprocal stabilization of ABL and TAZ regulates osteoblastogenesis through transcription factor RUNX2.

ABSTRACT: Cellular identity in metazoan organisms is frequently established through lineage-specifying transcription factors, which control their own expression through transcriptional positive feedback, while antagonizing the developmental networks of competing lineages. Here, we have uncovered a distinct positive feedback loop that arises from the reciprocal stabilization of the tyrosine kinase ABL and the transcriptional coactivator TAZ. Moreover, we determined that this loop is required for osteoblast differentiation and embryonic skeletal formation. ABL potentiated the assembly and activation of the RUNX2-TAZ master transcription factor complex that is required for osteoblastogenesis, while antagonizing PPAR?-mediated adipogenesis. ABL also enhanced TAZ nuclear localization and the formation of the TAZ-TEAD complex that is required for osteoblast expansion. Last, we have provided genetic data showing that regulation of the ABL-TAZ amplification loop lies downstream of the adaptor protein 3BP2, which is mutated in the craniofacial dysmorphia syndrome cherubism. Our study demonstrates an interplay between ABL and TAZ that controls the mesenchymal maturation program toward the osteoblast lineage and is mechanistically distinct from the established model of lineage-specific maturation.

SUBMITTER: Matsumoto Y

PROVIDER: S-EPMC5127668 | biostudies-literature | 2016 Dec

REPOSITORIES: biostudies-literature

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Reciprocal stabilization of ABL and TAZ regulates osteoblastogenesis through transcription factor RUNX2.

Matsumoto Yoshinori Y La Rose Jose J Kent Oliver A OA Wagner Melany J MJ Narimatsu Masahiro M Levy Aaron D AD Omar Mitchell H MH Tong Jiefei J Krieger Jonathan R JR Riggs Emily E Storozhuk Yaryna Y Pasquale Julia J Ventura Manuela M Yeganeh Behzad B Post Martin M Moran Michael F MF Grynpas Marc D MD Wrana Jeffrey L JL Superti-Furga Giulio G Koleske Anthony J AJ Pendergast Ann Marie AM Rottapel Robert R

The Journal of clinical investigation 20161031 12

Cellular identity in metazoan organisms is frequently established through lineage-specifying transcription factors, which control their own expression through transcriptional positive feedback, while antagonizing the developmental networks of competing lineages. Here, we have uncovered a distinct positive feedback loop that arises from the reciprocal stabilization of the tyrosine kinase ABL and the transcriptional coactivator TAZ. Moreover, we determined that this loop is required for osteoblast ...[more]

PMID: 27797343

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Project description:BACKGROUND: The mineralized skeleton is a major evolutionary novelty that has contributed to the impressive morphological diversifications of the vertebrates. Essential to bone biology is the solidified extracellular matrix secreted by highly specialized cells, the osteoblasts. We now have a rather complete view of the events underlying osteogenesis, from a cellular, molecular, genetic, and epigenetic perspective. Because this knowledge is still largely restricted to mammals, it is difficult, if not impossible, to deduce the evolutionary history of the regulatory network involved in osteoblasts specification and differentiation. In this study, we focused on the transcriptional regulators Runx2 and VDR (the Vitamin D Receptor) that, in mammals, directly interact together and stabilize complexes of co-activators and chromatin remodellers, thereby allowing the transcriptional activation of target genes involved in extracellular matrix mineralization. Using a combination of functional, biochemical, and histological approaches, we have asked if the interaction observed between Runx2 and VDR represents a recent mammalian innovation, or if it results from more ancient changes that have occurred deep in the vertebrate lineage. RESULTS: Using immunohistochemistry and in situ hybridization in developing embryos of chick, frog and teleost fishes, we have revealed that the co-expression of Runx2 and VDR in skeletal elements has been particularly strengthened in the lineage leading to amniotes. We show that the teleost Runx2 orthologue as well as the three mammalian Runx1, Runx2 and Runx3 paralogues are able to co-immunoprecipitate with the VDR protein present in nuclear extracts of rat osteoblasts stimulated with 1alpha,25-dihydroxyvitamin D3. In addition, the teleost Runx2 can activate the transcription of the mammalian osteocalcin promoter in transfection experiments, and this response can be further enhanced by 1alpha,25-dihydroxyvitamin D3. Finally, using pull-down experiments between recombinant proteins, we show that the VDR homologue from teleosts, but not from ascidians, is able to directly interact with the mammalian Runx2 homologue. CONCLUSIONS: We propose an evolutionary scenario for the assembly of the molecular machinery involving Runx2 and VDR in vertebrates. In the last common ancestor of actinopterygians and sacropterygians, the three Runx paralogues possessed the potential to physically and functionally interact with the VDR protein. Therefore, 1alpha,25-dihydroxyvitamin D3 might have been able to modulate the transcriptional activity of Runx1, Runx2 or Runx3 in the tissues expressing VDR. After the split from amphibians, in the lineage leading to amniotes, Runx2 and VDR became robustly co-expressed in developing skeletal elements, and their regulatory interaction was incorporated in the genetic program involved in the specification and differentiation of osteoblasts.

Dataset Information

Reciprocal stabilization of ABL and TAZ regulates osteoblastogenesis through transcription factor RUNX2.

Publications

Reciprocal stabilization of ABL and TAZ regulates osteoblastogenesis through transcription factor RUNX2.

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