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Skeletal cell YAP and TAZ redundantly promote bone development by regulation of collagen I expression and organization

Christopher D. Kegelman, Devon E. Mason, James H. Dawahare, Genevieve D. Vigil, Scott S. Howard, Teresita M. Bellido, Alexander G. Robling, Joel D. Boerckel
doi: https://doi.org/10.1101/143982
Christopher D. Kegelman
1Departments of Orthopaedic Surgery and Bioengineering, University of Pennsylvania, Philadelphia, PA
2Department of Aerospace and Mechanical Engineering, University of Notre Dame, Notre Dame, IN
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Devon E. Mason
1Departments of Orthopaedic Surgery and Bioengineering, University of Pennsylvania, Philadelphia, PA
2Department of Aerospace and Mechanical Engineering, University of Notre Dame, Notre Dame, IN
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James H. Dawahare
2Department of Aerospace and Mechanical Engineering, University of Notre Dame, Notre Dame, IN
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Genevieve D. Vigil
3Department of Electrical Engineering, University of Notre Dame, Notre Dame, IN
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Scott S. Howard
3Department of Electrical Engineering, University of Notre Dame, Notre Dame, IN
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Teresita M. Bellido
4Department of Anatomy and Cell Biology, Indiana University School of Medicine, Indianapolis, IN
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Alexander G. Robling
4Department of Anatomy and Cell Biology, Indiana University School of Medicine, Indianapolis, IN
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Joel D. Boerckel
1Departments of Orthopaedic Surgery and Bioengineering, University of Pennsylvania, Philadelphia, PA
2Department of Aerospace and Mechanical Engineering, University of Notre Dame, Notre Dame, IN
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  • For correspondence: jboercke@nd.edu
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ABSTRACT

The functions of the transcriptional co-activators YAP and TAZ in bone are controversial. Each has been observed to either promote or inhibit osteogenesis in vitro, while their roles in bone development are unknown. Here we report that combinatorial YAP/TAZ deletion from skeletal cells in mice caused osteogenesis imperfecta with severity dependent on targeted cell lineage and allele dosage. Osteocyte-conditional deletion impaired bone accrual and matrix collagen, while allele dosage-dependent deletion from all osteogenic lineage cells caused spontaneous fractures, with neonatal lethality only in dual homozygous knockouts. We identified putative target genes whose mutation in humans causes osteogenesis imperfecta and which contain promoter-proximate binding domains for the YAP/TAZ co-effector, TEAD4. Two candidates, Col1a1 and SerpinH1, exhibited reduced expression upon either YAP/TAZ deletion or YAP/TAZ-TEAD inhibition by verteporfin. Together, these data demonstrate that YAP and TAZ redundantly promote bone matrix development and implicate YAP/TAZ-mediated transcriptional regulation of collagen in osteogenesis imperfecta.

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Posted May 30, 2017.
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Skeletal cell YAP and TAZ redundantly promote bone development by regulation of collagen I expression and organization
Christopher D. Kegelman, Devon E. Mason, James H. Dawahare, Genevieve D. Vigil, Scott S. Howard, Teresita M. Bellido, Alexander G. Robling, Joel D. Boerckel
bioRxiv 143982; doi: https://doi.org/10.1101/143982
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Skeletal cell YAP and TAZ redundantly promote bone development by regulation of collagen I expression and organization
Christopher D. Kegelman, Devon E. Mason, James H. Dawahare, Genevieve D. Vigil, Scott S. Howard, Teresita M. Bellido, Alexander G. Robling, Joel D. Boerckel
bioRxiv 143982; doi: https://doi.org/10.1101/143982

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