A core transcriptional network composed of Pax2/8, Gata3 and Lim1 regulates key players of pro/mesonephros morphogenesis

Abstract

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.

Early formation of the Müllerian duct is regulated by sequential actions of BMP/Pax2 and FGF/Lim1 signaling

“…BMP signals are essential for MD specification by regulating Pax2 expression Previous studies reported that Lim1 acts downstream of Pax2 in several developmental contexts, including the development of mouse pronephros (Boualia et al, 2013;Bouchard et al, 2002). We therefore investigated whether Pax2 expression in the MFR was required for the expression of Lim1 during MD development.…”

Pax genes in renal development, disease and regeneration

“…Recent studies have explored the gene regulatory networks downstream of Pax genes in the renal system. In the nephric duct, Pax2/8 were found to regulate the transcription factor genes Gata3 and Lhx1, which together with Pax proteins, turn on the downstream transcriptional program necessary for renal morphogenesis ( Figure 2) [50]. Gata3 acts as a driver of nephric duct guidance and morphogenesis in the mouse embryo [51], while Lhx1 plays an M a n u s c r i p t important role in nephric duct elongation and survival [52][53][54][55].…”

“…Gata3 acts as a driver of nephric duct guidance and morphogenesis in the mouse embryo [51], while Lhx1 plays an M a n u s c r i p t important role in nephric duct elongation and survival [52][53][54][55]. Among the key developmental regulators acting downstream of the Pax2/8-Gata3-Lhx1 gene regulatory core [50] are effector genes such as Emx2 [56], Hnf1 [57] and Plac8 [50] ( Figure 2). Emx2 expression is regulated by Pax2 and is involved in a positive feedback loop that maintains Pax2 expression in the nephric duct and ureters [58].…”

“…Pax genes act on this system at several distinct levels during kidney development ( Figure 2). In the nephric duct, Ret is a direct regulatory target of Gata3 [50,51,64]. The Pax2/8-Gata3 cascade is therefore necessary to establish the responsiveness of the nephric duct to kidney induction.…”

“…The Pax2/8-Gata3 cascade is therefore necessary to establish the responsiveness of the nephric duct to kidney induction. Interestingly, Pax2/8 from the nephric duct also act indirectly on the maintenance of Gdnf in the metanephric mesenchyme through the Pax2/8-Lhx1-Npnt cascade [50,64]. Epithelial Npnt is the ligand for mesenchymal α8β1 integrin [65].…”