Gene regulatory network of renal primordium development

Abstract

Animal development progresses through the stepwise deployment of gene regulatory networks (GRN) encoded in the genome. Comparative analyses in different species and organ systems have revealed that GRN blueprints are composed of subcircuits with stereotypical architectures that are often reused as modular units. In this review, we report the evidence for the GRN underlying renal primordium development. In vertebrates, renal development is initiated by the induction of a field of intermediate mesoderm cells competent to undergo lineage specification and nephric (Wolffian) duct formation. Definition of the renal field leads to the activation of a core regulatory subcircuit composed of the transcription factors Pax2/8, Gata3 and Lim1. These transcription factors turn on a second layer of transcriptional regulators while also activating effectors of tissue morphogenesis and cellular specialization. Elongation and connection of the nephric duct to the cloaca (bladder/urethra primordium) is followed by metanephric kidney induction through signals emanating from the metanephric mesenchyme. Central to this process is the activation and positioning of the glial cell line-derived neurotrophic factor (Gdnf)-Ret signaling pathway by network subcircuits located in the mesenchyme and epithelial tissues of the caudal trunk. Evidence shows that each step of the renal primordium developmental program is regulated by structured GRN subunits organized in a hierarchical manner. Understanding the structure and dynamics of the renal GRN will help us understand the intrinsic phenotypical variability of congenital anomalies of the kidney and urinary tract and guide our approaches to regenerative medicine.

Prenatal dexamethasone-induced programmed hypertension and renal programming

“…Because renal programming events may manifest as a low nephron endowment in diet-induced programming models [17], and because we previously observed that DEX can impair nephrogenesis [9], we analyzed a panel of genes that has previously been reported to be relevant to kidney development [18,19]. As shown in Table 2, Fgf10, Wt1, Gfra1, Eya1, Gata3, Kirrel, Etv4, Lhx1, Bmp2, and Cdh6 were found to be modified above the chosen threshold in the kidneys of 1-week-old offspring.…”

Maternal fructose-intake-induced renal programming in adult male offspring

“…Since renal programming may manifest as a low nephron endowment in diet-induced programming models [2][3][4][5], literature was used to identify relevant target genes crucial for kidney development [16,17]. As shown in Table 3, Slit2, Spry3, Pod1, Col4a1, Col4a2, Col4a4, Wnt9b, Lif, Fgf2, Fgf20, Notch2, Jnk3 and Cdh6 were found modified above the chosen threshold in the kidney of offspring at 1 day of age to maternal HF exposure.…”

“…Furthermore, epigenetic regulation is a proposed mechanism contributing to developmental programming [17]. We analyzed five groups of epigenetic regulators in the kidneys of offspring at 1 day of age to maternal HF diet.…”

Pax genes in renal development, disease and regeneration

“…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].…”

“…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.…”