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RECQL4 Regulates p53 Function In Vivo During Skeletogenesis
Author(s) -
Lu Linchao,
Harutyunyan Karine,
Jin Weidong,
Wu Jianhong,
Yang Tao,
Chen Yuqing,
Joeng Kyu Sang,
Bae Yangjin,
Tao Jianning,
Dawson Brian C,
Jiang MingMing,
Lee Brendan,
Wang Lisa L
Publication year - 2015
Publication title -
journal of bone and mineral research
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.882
H-Index - 241
eISSN - 1523-4681
pISSN - 0884-0431
DOI - 10.1002/jbmr.2436
Subject(s) - biology , mutation , loss function , phenotype , genetics , mutant , in vivo , gene , cancer research
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 RECQL4 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 Recql4 conditional knockout mice targeting the skeletal lineage. Inactivation of Recql4 using the Prx1‐Cre transgene led to limb abnormalities and craniosynostosis mimicking the major bone findings in human RECQL4 patients. These Prx1‐Cre + ;Recql4 fl/fl mice as well as Col2a1‐Cre + ;Recql4 fl/fl mice exhibited growth plate defects and an increased p53 response in affected tissues. Inactivation of Trp53 in these Recql4 mutants resulted in genetic rescue of the skeletal phenotypes, indicating an in vivo interaction between Recql4 and Trp53 , and p53 activation as an underlying mechanism for the developmental bone abnormalities in RECQL4 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