RECQL4 Regulates p53 Function In Vivo During Skeletogenesis. (June 2015)

• Record Type: Journal Article
• Authors: Lu, Linchao; Harutyunyan, Karine; Jin, Weidong; Wu, Jianhong; Yang, Tao; Chen, Yuqing; Joeng, Kyu Sang; Bae, Yangjin; Tao, Jianning; Dawson, Brian C; Jiang, Ming‐Ming; Lee, Brendan; Wang, Lisa L
• Is Part Of: Journal of bone and mineral research. Volume 30:Number 6(2015:Jun.)
• Page Start: 1077
• Page End: 1089
• Publication Date: 2015-06
• Subjects: Bones -- Metabolism -- Periodicals; Mineral metabolism -- Periodicals; 612.392
• DOI: 10.1002/jbmr.2436
• Languages: English
• ISSNs: 0884-0431

Abstract

<abstract abstract-type="main" xml:lang="en"> <title>ABSTRACT</title> <sec id="jbmr2436-sec-0001" sec-type="section"> <p>RECQ DNA helicases play critical roles in maintaining genomic stability, but their role in development has been less well studied. Rothmund‐Thomson syndrome, RAPADILINO, and Baller‐Gerold syndrome are rare genetic disorders caused by mutations in the <italic>RECQL4</italic> gene. These patients have significant skeletal developmental abnormalities including radial ray, limb and craniofacial defects. To investigate the role of Recql4 in the developing skeletal system, we generated <italic>Recql4</italic> conditional knockout mice targeting the skeletal lineage. Inactivation of <italic>Recql4</italic> using the <italic>Prx1‐Cre</italic> transgene led to limb abnormalities and craniosynostosis mimicking the major bone findings in human <italic>RECQL4</italic> patients. These <italic>Prx1‐Cre<sup>+</sup>;Recql4<sup>fl/fl</sup></italic> mice as well as <italic>Col2a1‐Cre<sup>+</sup>;Recql4<sup>fl/fl</sup></italic> mice exhibited growth plate defects and an increased p53 response in affected tissues. Inactivation of <italic>Trp53</italic> in these <italic>Recql4</italic> mutants resulted in genetic rescue of the skeletal phenotypes, indicating an in vivo interaction between <italic>Recql4</italic> and <italic>Trp53</italic>, and p53 activation as an underlying mechanism for the developmental bone abnormalities in <italic>RECQL4</italic> disorders. Our findings show that RECQL4 is critical for skeletal development by modulating p53 activity in vivo. © 2015 American Society for Bone and Mineral Research</p> </sec> </abstract>