Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: UNIPROT:P41181 (collecting duct)
 5,183 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

We have purified a protein present in a conditioned medium derived from the metanephric mesenchyme that supports non-branching growth and epithelial differentiation of the isolated ureteric bud (UB) independent of glial cell line-derived neurotrophic growth factor (GDNF). By sequential liquid chromatography, together with protein microsequencing, the protein was identified as heregulin (HRG)alpha. The addition of recombinant HRG to the isolated UB grown in three-dimensional culture confirmed the proliferative activity of HRG. In branching UBs induced by whole metanephric mesenchyme cell-conditioned medium, proliferating cells were localized at ampullae, where a binding receptor for GDNF, GFRalpha1, was found. In HRG-induced UBs, however, the expression of GFRalpha1 was down-regulated, and proliferating cells were distributed throughout the structure. Electron microscopic examination of the HRG-induced UB revealed the presence of structurally mature and polarized epithelial cells reminiscent of the epithelial cells found in the stalk portion of the branching UB. cDNA array analysis further revealed that genes ontologically classified as developmental were down-regulated by HRG, whereas those involved in transport were up-regulated. For example, the mRNA for the GDNF receptors, GFRalpha1 and ret9, was down-regulated, whereas the mRNA for collecting duct transporters, such as urea transporter2, aquaporin3, and sodium-hydrogen exchanger2 was up-regulated in HRG-treated UBs compared with UBs grown in the presence of branch-promoting factors. Moreover, HRG promoted growth of UBs cultured in the absence of GDNF. Taken together, the data suggest that HRG supports UB epithelial cell differentiation and non-GDNF-dependent growth, raising the possibility that this kind of activity plays a role in the growth and differentiation of the stalk portion of the branching epithelial UB.
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PMID:Heregulin induces glial cell line-derived neurotrophic growth factor-independent, non-branching growth and differentiation of ureteric bud epithelia. 1618 43

Kidney organogenesis depends on reciprocal interactions between the ureteric bud (UB) and the metanephric mesenchyme (MM) to form the UB-derived collecting system and MM-derived nephron. With the advent of in vitro systems, it is clear that UB branching can occur independently of MM contact; however, little has been done to detail the role of MM cellular contact in this process. Here, a model system in which the cultured isolated UB is recombined with uninduced MM is used to isolate the effects of the MM progenitor tissue on the development and maturation of the collecting system. By morphometrics, we demonstrate that cellular contact with the MM is required for vectorial elongation of stalks and tapering of luminal caliber of UB-derived tubules. Expression analysis of developmentally significant genes indicates the cocultured tissue is most similar to an embryonic day 19 (E19) kidney. The likely major contributor to this is the functional maturation of the collecting duct and proximal nephron segments in the UB-induced MM, as measured by quantitative PCR, of the collecting duct-specific arginine vasopressin receptor and the nephron tubule segment-specific organic anion transporter OAT1, Na-P(i) type 2 cotransporter, and Tamm-Horsfall protein gene expressions. However, expression of aquaporin-2 is upregulated similarly in isolated UB and cocultured tissue, suggesting that some aspects of functional maturation can occur independently of MM cellular contact. In addition to its sculpting effects, the MM normalized a "branchless" UB morphology induced by FGF7 or heregulin in isolated UB culture. The morphological changes induced by the MM were accompanied by a reassignment of GFRalpha1 (a receptor for GDNF) to tips. Such "quality control" by the MM of UB morphology may provide resiliency to the branching program. This may help to explain a number of knockout phenotypes in which branching and/or cystic defects are less impressive than expected. A second hit in the MM may thus be necessary to make these defects fully apparent.
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PMID:The instructive role of metanephric mesenchyme in ureteric bud patterning, sculpting, and maturation and its potential ability to buffer ureteric bud branching defects. 1972 49