Modulation of biological regulatory networks during nephrogenesis.
Mesenchymal-to-epithelial transition is an important biological event during the course of renal cell differentiation as condensing mesenchyme gives rise to tubuloepithelial structures. Wilms' tumor suppressor gene (Wt1) has been identified as a master regulator of the complex genetic events that mediate mesenchymal transdifferentiation. Evidence is summarized here showing that the tightly regulated series of genetic and biochemical events during nephrogenesis is disrupted by superactivation of aryl hydrocarbon receptor (Ahr) by benzo(a)pyrene (BaP), a ubiquitous polycyclic aromatic hydrocarbon and renal carcinogen (Falahatpisheh and Ramos, 2003). Nephron formation is inhibited by BaP, a response that involves inhibition of metanephric cell differentiation and shifts in the relative abundance of Wt1 splice variants. A systems biology paradigm that combined approaches from genomics, transcriptomics, and bioinformatics revealed that the global response of murine metanephric cultures to BaP involves downregulation of Ahr and disruption of downstream targets of Wt1. Discrete networks of genetic regulation were resolved using Boolean idealizations and included genes involved in renal cell differentiation and metabolic control. This work has established a role for Ahr in renal cell differentiation and kidney development and resolved putative molecular interactions between Ahr and Wt1.
Ramos
Kenneth S
KS
Department of Biochemistry and Molecular Biology, Center for Genetics and Molecular Medicine, University of Louisville School of Medicine, Louisville, KY 40292, USA. kenneth.ramos@louisville.edu
Hadi Falahatpisheh
M
M
Nanez
Adrian
A
He
Qiang
Q
D000818:Animals; D004847:Epithelial Cells / Q000502:physiology; D005260:Female; D016162:Genes, Wilms Tumor / Q000502:physiology; D006801:Humans; D007668:Kidney / Q000196:embryology*; D059630:Mesenchymal Stem Cells / Q000502:physiology; D009399:Nephrons / Q000196:embryology*; D011247:Pregnancy; D018336:Receptors, Aryl Hydrocarbon / Q000235:genetics / Q000502:physiology
D018336:Receptors, Aryl Hydrocarbon