title: RECQL4 Regulates p53 Function In Vivo During Skeletogenesis.
abstract: 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.
authors.affiliation: Texas Children's Cancer Center, Department of Pediatrics, Houston, TX, USA.
authors.forename: Linchao
authors.initials: L
authors.lastname: Lu
authors.affiliation: Texas Children's Cancer Center, Department of Pediatrics, Houston, TX, USA.
authors.forename: Karine
authors.initials: K
authors.lastname: Harutyunyan
authors.affiliation: Texas Children's Cancer Center, Department of Pediatrics, Houston, TX, USA.
authors.forename: Weidong
authors.initials: W
authors.lastname: Jin
authors.affiliation: Texas Children's Cancer Center, Department of Pediatrics, Houston, TX, USA.
authors.forename: Jianhong
authors.initials: J
authors.lastname: Wu
authors.affiliation: Center for Skeletal Diseases and Tumor Metastasis, Van Andel Research Institute, Grand Rapids, MI 49503, USA.
authors.forename: Tao
authors.initials: T
authors.lastname: Yang
authors.affiliation: Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX, USA.|Howard Hughes Medical Institute, Houston, TX, USA.
authors.forename: Yuqing
authors.initials: Y
authors.lastname: Chen
authors.affiliation: Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX, USA.
authors.forename: Kyu Sang
authors.initials: KS
authors.lastname: Joeng
authors.affiliation: Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX, USA.
authors.forename: Yangjin
authors.initials: Y
authors.lastname: Bae
authors.affiliation: Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX, USA.
authors.forename: Jianning
authors.initials: J
authors.lastname: Tao
authors.affiliation: Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX, USA.|Howard Hughes Medical Institute, Houston, TX, USA.
authors.forename: Brian C
authors.initials: BC
authors.lastname: Dawson
authors.affiliation: Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX, USA.|Howard Hughes Medical Institute, Houston, TX, USA.
authors.forename: Ming-Ming
authors.initials: MM
authors.lastname: Jiang
authors.affiliation: Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX, USA.|Howard Hughes Medical Institute, Houston, TX, USA.
authors.forename: Brendan
authors.initials: B
authors.lastname: Lee
authors.affiliation: Texas Children's Cancer Center, Department of Pediatrics, Houston, TX, USA.
authors.forename: Lisa L
authors.initials: LL
authors.lastname: Wang
mesh_terms: D001003:Anal Canal / Q000002:abnormalities / Q000378:metabolism / Q000473:pathology; D000818:Animals; D001846:Bone Development; D003398:Craniosynostoses / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D004392:Dwarfism / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D006344:Heart Septal Defects, Atrial / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D006801:Humans; D017880:Limb Deformities, Congenital / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D051379:Mice; D008822:Mice, Transgenic; D009154:Mutation; D010329:Patella / Q000002:abnormalities / Q000378:metabolism / Q000473:pathology; D011884:Radius / Q000002:abnormalities / Q000378:metabolism / Q000473:pathology; D053484:RecQ Helicases / Q000235:genetics / Q000378:metabolism*; D011038:Rothmund-Thomson Syndrome / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D016159:Tumor Suppressor Protein p53 / Q000235:genetics / Q000378:metabolism*
chemical_list: D016159:Tumor Suppressor Protein p53; D053484:RecQ Helicases
keywords: RECQL4; Rothmund-Thomson syndrome; cartilage; genetic animal models; skeletal development