Patterns of differentiation of renin lineage cells during nephrogenesis

Developmentally heterogeneous renin expressing cells serve as progenitors for mural, glomerular and tubular cells during nephrogenesis and are collectively termed renin lineage cells (RLCs). In this study, we quantified different renal vascular and tubular cell types based on specific markers, assessed proliferation, and de-novo differentiation in the RLC population. We used kidney sections of mRenCre-mT/mG mice throughout nephrogenesis. Marker positivity was evaluated in whole digitalized sections. At embryonic day 16, RLCs appeared in the developing kidney, and expression of all stained markers in RLCs was observed. The proliferation rate of RLCs did not differ from the proliferation rate of non-RLCs. The RLCs expanded mainly by de-novo differentiation (neogenesis). The fractions of RLCs originating from the stromal progenitors of the metanephric mesenchyme (renin producing cells, vascular smooth muscle cells, mesangial cells) decreased during nephrogenesis. In contrast, aquaporin 2 positive RLCs in the collecting duct system that embryonically emerges almost exclusively from the ureteric bud, expanded postpartum. The cubilin positive RLC fraction in the proximal tubule, deriving from the cap mesenchyme, remained constant. During nephrogenesis, RLCs were continuously detectable in the vascular and tubular compartments of the kidney. Therein, various patterns of RLC differentiation that depend on the embryonic origin of the cells were identified.

Transcription Factor 21 Is Required for Branching Morphogenesis and Regulates the Gdnf-Axis in Kidney Development

BackgroundThe mammalian kidney develops through reciprocal inductive signals between the metanephric mesenchyme and ureteric bud. Transcription factor 21 (Tcf21) is highly expressed in the metanephric mesenchyme, including Six2-expressing cap mesenchyme and Foxd1-expressing stromal mesenchyme. Tcf21 knockout mice die in the perinatal period from severe renal hypodysplasia. In humans, Tcf21 mRNA levels are reduced in renal tissue from human fetuses with renal dysplasia. The molecular mechanisms underlying these renal defects are not yet known.MethodsUsing a variety of techniques to assess kidney development and gene expression, we compared the phenotypes of wild-type mice, mice with germline deletion of the Tcf21 gene, mice with stromal mesenchyme–specific Tcf21 deletion, and mice with cap mesenchyme–specific Tcf21 deletion.ResultsGermline deletion of Tcf21 leads to impaired ureteric bud branching and is accompanied by downregulated expression of Gdnf-Ret-Wnt11, a key pathway required for branching morphogenesis. Selective removal of Tcf21 from the renal stroma is also associated with attenuation of the Gdnf signaling axis and leads to a defect in ureteric bud branching, a paucity of collecting ducts, and a defect in urine concentration capacity. In contrast, deletion of Tcf21 from the cap mesenchyme leads to abnormal glomerulogenesis and massive proteinuria, but no downregulation of Gdnf-Ret-Wnt11 or obvious defect in branching.ConclusionsOur findings indicate that Tcf21 has distinct roles in the cap mesenchyme and stromal mesenchyme compartments during kidney development and suggest that Tcf21 regulates key molecular pathways required for branching morphogenesis.