Novel Regulators of Kidney Development from the Tips of the Ureteric Bud

Abstract

Mammalian nephrogenesis depends on the interaction between the ureteric bud and the metanephric mesenchyme. As the ureteric bud undergoes branching and segmentation, the stalks differentiate into the collecting system of the mature kidney, while the tip cells interact with the adjacent cells of the metanephric mesenchyme, inducing their conversion into nephrons. This induction is mediated by secreted factors. For identifying novel mediators, the tips of the ureteric tree were isolated and microarray analyses were performed using manually refined, multistep gene ontology annotations. For identifying conserved factors, two databases were developed, one from mouse E 12.5 and one from rat E 13.5 ureteric buds. The overlap of mouse and rat data sets yielded 20 different transcripts that were enriched in the ureteric bud compared with metanephric mesenchyme and predicted to code for secreted proteins. Real-time reverse transcriptase-PCR and in situ hybridization confirmed these identifications. One of the genes that was highly specific to the ureteric bud tip was cytokine-like factor 1 (CLF-1). Recombinant CLF-1 in complex with its physiologic ligand, cardiotrophin-like cytokine (CLC), triggered phosphorylation of signal transducer and activator of transcription 3 in mesenchyme, a pathway characteristic of mesenchymal-to-epithelial conversion. Indeed, when applied to isolated rat metanephric mesenchyme, CLF-1/CLC (3 nM) induced mature nephron structures expressing glomerular and tubular markers. These results underline the power of this first comprehensive gene expression analysis of the ureteric bud tip to identify bioactive molecules.

Co-expression of FBN1 with mesenchyme-specific genes in mouse cell lines: implications for phenotypic variability in Marfan syndrome

“…25 In addition, we considered data sets from developing mouse kidney (E12.5; GEO Profiles accession no. GDS1583) 26 and from developing mouse gastrointestinal tract (E18.5; GEO Profiles accession no. GDS2699).…”

“…The transition has been analysed separately in developing mouse kidney 26 and gastrointestinal tract. 27 Fbn1 expression was strongly associated with mesenchyme in these data sets.…”

GDNF/Ret signaling and the development of the kidney

“…(70) However, soon after the UB emerges it becomes divided into distinct tip and trunk domains. In addition to Ret and Gfra1, there are many other genes expressed specifically in the tip domain but not in the trunks, including Wnt11, Crlf1, and CXCL14 to name a few; (71,72) conversely, different genes are expressed only in the trunks (e.g. Wnt7b and collagen XVIII).…”

The Interface Between Generating Renal Tubules and a Polyester Fleece in Comparison to the Interstitium of the Developing Kidney

“…20,25 This molecular process results in the formation of a comma-shaped body as a first morphological sign of a developing nephron. Thus, the interstitium at the ampulla tip was analyzed by SEM (Figs.…”