Hedgehog-GLI signaling inFoxd1-positive stromal cells promotes nephrogenesis Via TGFβ signaling

Abstract

Normal kidney function depends on the proper development of the nephron: the functional unit of the kidney. Reciprocal signaling interactions between the stroma and nephron progenitor compartment have been proposed to control nephron development. Here, we show that removal of hedgehog intracellular effector smoothened (-deficient mutants) in the cortical stroma results in an abnormal renal capsule, and an expanded nephron progenitor domain with an accompanying decrease in nephron number via a block in epithelialization. We show that stromal-hedgehog-Smo signaling acts through a GLI3 repressor. Whole-kidney RNA sequencing and analysis of FACS-isolated stromal cells identified impaired TGFβ2 signaling in -deficient mutants. We show that neutralization and knockdown of TGFβ2 in explants inhibited nephrogenesis. In addition, we demonstrate that concurrent deletion of in stromal and nephrogenic cells results in decreased nephron formation and an expanded nephrogenic precursor domain similar to that observed in-deficient mutant mice. Together, our data suggest a mechanism whereby a stromal hedgehog-TGFβ2 signaling axis acts to control nephrogenesis.

Activin Is Superior to BMP7 for Efficient Maintenance of Human iPSC-Derived Nephron Progenitors

“…(2016) reported maintenance of NPCs from human embryos utilizing BMP7 and a BMP receptor inhibitor, resulting in SMAD1 inhibition. Meanwhile, expression of activin receptor type II or phosphorylated Smad2 in the nephron progenitor regions was reported in mice (Rowan et al., 2018). Furthermore, deletion of GDF11 , which is expressed in nephron progenitors and the ureteric bud, led to kidney hypoplasia (Esquela and Lee, 2003).…”

Chromatin accessibility and microRNA expression in nephron progenitor cells during kidney development

“…We find that miRNA with the greatest changes in expression between E14.5 and P0 (up or down) are those that regulate pathways with key roles in nephrogenesis ( Figure 4, Supplemental figure 5 ). For instance, Tgf-β is secreted by surrounding stromal cells to promote nephron progenitor differentiation (Rowan et al, 2018), and we note reduced expression among nephron progenitor miRNA targeting the downstream effectors of the “TGF-β signaling pathway” (KEGG pathway mmu04350, p-value 1.45e -6 ). The “MAPK signaling pathway” (mmu04010) influences organization and priming of nephron progenitors for differentiation, and it regulates their interactions with the extracellular matrix (ECM) via Itgα8 (Ihermann-Hella et al, 2018).…”

Expansion of the renal capsular stroma, ureteric bud branching defects and cryptorchidism in mice with Wilms tumor 1 gene deletion in the stromal compartment of the developing kidney

“…In order to determine the molecular changes that may cause the branching defects in Wt1cKO kidneys, we analysed the expression of genes encoding factors previously implicated in the development and crosstalk of the different renal lineages [8] on sections of E12.5, E13.5, and E14.5 kidneys. We did not find changes in the expression of Axin2 – target of WNT signalling [35,36]; of Ptch1 – target of sonic hedgehog (SHH) signalling [37,38]; of the bone morphogenetic protein (BMP) ligand genes, Bmp4 and Bmp7 , of the BMP antagonist Bmper ; of Id2 and Id4 – targets of BMP signalling [39,40]; of the fibrocyte growth factor (FGF) ligand genes Fgf7 and Fgf10 ; or of the targets of FGF signalling, Etv4 and Etv5 [41–43] (supplementary material, Figures S6 and S7). Other stromal genes and regulators such as Tcf21 , Akap12 , Decorin , and Fat4 [8] were not changed at E14.5 either (supplementary material, Figure S8).…”