title: Calcium/NFAT signalling promotes early nephrogenesis.
abstract: A number of Wnt genes are expressed during, and are known to be essential for, early kidney development. It is typically assumed that their products will act through the canonical β-catenin signalling pathway. We have found evidence that suggests canonical Wnt signalling is not active in the early nephrogenic metanephric mesenchyme, but instead provide expressional and functional evidence that implicates the non-canonical Calcium/NFAT Wnt signalling pathway in nephrogenesis. Members of the NFAT (Nuclear Factor Activated in T cells) transcription factor gene family are expressed throughout murine kidney morphogenesis and NFATc3 is localised to the developing nephrons. Treatment of kidney rudiments with Cyclosporin A (CSA), an inhibitor of Calcium/NFAT signalling, decreases nephron formation--a phenotype similar to that in Wnt4(-/-) embryos. Treatment of Wnt4(-/-) kidneys with Ionomycin, an activator of the pathway, partially rescues the phenotype. We propose that the non-canonical Calcium/NFAT Wnt signalling pathway plays an important role in early mammalian renal development and is required for complete MET during nephrogenesis, potentially acting downstream of Wnt4.
authors.affiliation: MRC Human Genetics Unit, Institute of Genetics & Molecular Medicine, Western General Hospital, Crewe Road, Edinburgh EH4 2XU, UK. sb3158@columbia.edu
authors.forename: S F
authors.initials: SF
authors.lastname: Burn
authors.forename: A
authors.initials: A
authors.lastname: Webb
authors.forename: R L
authors.initials: RL
authors.lastname: Berry
authors.forename: J A
authors.initials: JA
authors.lastname: Davies
authors.forename: A
authors.initials: A
authors.lastname: Ferrer-Vaquer
authors.forename: A K
authors.initials: AK
authors.lastname: Hadjantonakis
authors.forename: N D
authors.initials: ND
authors.lastname: Hastie
authors.forename: P
authors.initials: P
authors.lastname: Hohenstein
mesh_terms: D000818:Animals; D001483:Base Sequence; D020013:Calcium Signaling / Q000187:drug effects / Q000502:physiology*; D016572:Cyclosporine / Q000494:pharmacology; D015342:DNA Probes / Q000235:genetics; D018507:Gene Expression Regulation, Developmental; D015759:Ionomycin / Q000494:pharmacology; D007668:Kidney / Q000187:drug effects / Q000196:embryology* / Q000378:metabolism*; D051379:Mice; D018345:Mice, Knockout; D008822:Mice, Transgenic; D050778:NFATC Transcription Factors / Q000378:metabolism*; D010641:Phenotype; D015398:Signal Transduction / Q000187:drug effects / Q000502:physiology; D051153:Wnt Proteins / Q000172:deficiency / Q000235:genetics / Q000378:metabolism; D060528:Wnt4 Protein; D051176:beta Catenin / Q000378:metabolism
chemical_list: C495267:CTNNB1 protein, mouse; D015342:DNA Probes; D050778:NFATC Transcription Factors; C494009:Nfatc3 protein, mouse; C555581:WNT4 protein, human; D051153:Wnt Proteins; D060528:Wnt4 Protein; C555582:Wnt4 protein, mouse; D051176:beta Catenin; D015759:Ionomycin; D016572:Cyclosporine