A core transcriptional network composed of Pax2/8, Gata3 and Lim1 regulates key players of pro/mesonephros morphogenesis.
Translating the developmental program encoded in the genome into cellular and morphogenetic functions requires the deployment of elaborate gene regulatory networks (GRNs). GRNs are especially crucial at the onset of organ development where a few regulatory signals establish the different programs required for tissue organization. In the renal system primordium (the pro/mesonephros), important regulators have been identified but their hierarchical and regulatory organization is still elusive. Here, we have performed a detailed analysis of the GRN underlying mouse pro/mesonephros development. We find that a core regulatory subcircuit composed of Pax2/8, Gata3 and Lim1 turns on a deeper layer of transcriptional regulators while activating effector genes responsible for cell signaling and tissue organization. Among the genes directly affected by the core components are the key developmental molecules Nephronectin (Npnt) and Plac8. Hence, the pro/mesonephros GRN links together several essential genes regulating tissue morphogenesis. This renal GRN sheds new light on the disease group Congenital Anomalies of the Kidney and Urinary Tract (CAKUT) in that gene mutations are expected to generate different phenotypic outcomes as a consequence of regulatory network deficiencies rather than threshold effects from single genes.
Goodman Cancer Research Centre and Department of Biochemistry, McGill University, 1160 Pine Ave. W., Montreal, Quebec, Canada H3A 1A3.
Sami Kamel
SK
Boualia
Yaned
Y
Gaitan
Mathieu
M
Tremblay
Richa
R
Sharma
Julie
J
Cardin
Artur
A
Kania
Maxime
M
Bouchard
D000818:Animals; D002460:Cell Line; D050990:GATA3 Transcription Factor / Q000235:genetics*; D018507:Gene Expression Regulation, Developmental; D053263:Gene Regulatory Networks; D007668:Kidney / Q000002:abnormalities; D060850:LIM-Homeodomain Proteins / Q000235:genetics*; D008650:Mesonephros / Q000196:embryology* / Q000378:metabolism; D051379:Mice; D009024:Morphogenesis / Q000235:genetics; D051762:PAX2 Transcription Factor / Q000235:genetics*; D000072636:PAX8 Transcription Factor; D051761:Paired Box Transcription Factors / Q000235:genetics*; D014157:Transcription Factors / Q000235:genetics*
D050990:GATA3 Transcription Factor; C494748:Gata3 protein, mouse; D060850:LIM-Homeodomain Proteins; C499523:Lhx1 protein, mouse; D051762:PAX2 Transcription Factor; D000072636:PAX8 Transcription Factor; D051761:Paired Box Transcription Factors; C499496:Pax8 protein, mouse; D014157:Transcription Factors
CAKUT; CND; ChIP; GDNF; Gata3; Kidney development; Lim1; Pax2; Transcription; chromatin immunoprecipitation; common nephric duct; congenital anomalies of the kidney and urinary tract; glial cell line-derived neurotrophic factor