RECQL4 Regulates p53 Function in vivo During Skeletogenesis.

“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+ ;Recql4fl/fl mice as well as Col2a1-Cre+ ;Recql4fl/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.”

“Whole skeleton preparations of P0 mice showed that the forelimbs of Prx1-Cre+;Recql4fl/fl mice were severely foreshortened and deformed. Hindlimbs of these mutants were less affected but were also smaller and shorter compared to littermate controls”

“At three weeks of age, mutant mice that survived exhibited significantly smaller limbs, as well as abnormal ossification in the joint region of the hindlimbs. Prx1-Cre+;Recql4fl/fl mutants also displayed growth retardation”

“at E18.5, H&E staining of distal femur growth plates revealed that chondrocytes from Prx1-Cre+;Recql4fl/fl mice had significantly reduced cell density and increased cell size in the resting zone (RZ), proliferating zone (PZ) and hypertrophic zone (HZ) compared to littermate controls. At three weeks of age, mutant mice showed disorganized distal femur growth plates and abnormal chondrocyte morphology demonstrating increased cell size. It appears that inactivation of Recql4 in mesenchymal progenitor cells primarily affects the growth plate chondrocytes. These cartilage phenotypes correlate with the known expression of Recql4 in the developing cartilage and may contribute to the skeletal defects in the human RECQL4 disorders at least in the appendicular skeleton.”

Deletion of Recql4 resulted in increased apoptosis and decreased proliferation of growth plate cartilage cells.  Deletion of Recql4 results in increased levels of p53 which can result in DNA damage.