a p53-pax2 pathway in kidney development implications for nephrogenesis对nephrogenesis p53-pax2通路在肾脏发展的影响.pdfVIP

A p53-Pax2 Pathway in Kidney Development: Implications for Nephrogenesis 1,2 1,2 1 1 1 1 Zubaida Saifudeen *, Jiao Liu , Susana Dipp , Xiao Yao , Yuwen Li , Nathaniel McLaughlin , Karam Aboudehen1¤, Samir S. El-Dahr1,2 1 Section of Pediatric Nephrology, Department of Pediatrics, Tulane University Health Sciences Center, New Orleans, Louisiana, United States of America, 2 The Hypertension and Renal Center of Excellence, Tulane University Health Sciences Center, New Orleans, Louisiana, United States of America Abstract Congenital reduction in nephron number (renal hypoplasia) is a predisposing factor for chronic kidney disease and hypertension. Despite identification of specific genes and pathways in nephrogenesis, determinants of final nephron endowment are poorly understood. Here, we report that mice with germ-line p53 deletion (p53 2/ 2) manifest renal hypoplasia; the phenotype can be recapitulated by conditional deletion of p53 from renal progenitors in the cap mesenchyme (CMp53 2/ 2). Mice or humans with germ-line heterozygous mutations in Pax2 exhibit renal hypoplasia. Since both transcription factors are developmentally expressed in the metanephros, we tested the hypothesis that p53 and Pax2 cooperate in nephrogenesis. In this study, we provide evidence for the presence of genetic epistasis between p53 and Pax2: a) p53 2/ 2 and CMp53 2/ 2embryos express lower Pax2 mRNA and protein in nephron progenitors than their wild-type littermates; b) ChIP-Seq identified peaks of p53 occupancy in chromatin regions of the Pax2 promoter and gene in embryonic kidneys;