Calcium/NFAT signalling promotes early nephrogenesis

• Published in: Developmental biology 2011-04, Vol.352 (2), p.288-298
• Main Authors: Burn, S.F., Webb, A., Berry, R.L., Davies, J.A., Ferrer-Vaquer, A., Hadjantonakis, A.K., Hastie, N.D., Hohenstein, P.
• Format: Article
• Language: English
• Subjects: Animals; Base Sequence; beta Catenin - metabolism; Calcium; Calcium Signaling - drug effects; Calcium Signaling - physiology; cyclosporine; Cyclosporine - pharmacology; DNA Probes - genetics; Embryo; gene expression; Gene Expression Regulation, Developmental; genes; Ionomycin - pharmacology; Kidney; Kidney - drug effects; Kidney - embryology; Kidney - metabolism; Mice; Mice, Knockout; Mice, Transgenic; morphogenesis; Nephrogenesis; nephrons; NFAT; NFATC Transcription Factors - metabolism; Phenotype; signal transduction; Signal Transduction - drug effects; Signal Transduction - physiology; T-lymphocytes; transcription factors; Wnt Proteins - deficiency; Wnt Proteins - genetics; Wnt Proteins - metabolism; Wnt4; Wnt4 Protein
• ISSN: 0012-1606; 1095-564X
• DOI: 10.1016/j.ydbio.2011.01.033

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. ► No β-catenin activity can be detected in the early nephrogenic mesenchyme. ► Expressional and functional data implicate Ca2+/NFAT Wnt signalling in nephrogenesis. ► Disruption of the Ca2+/NFAT pathway disrupts kidney morphogenesis. ► Increased Ca2+ signalling partially rescues nephrogenesis in Wnt4 knockout mice. ► We propose Ca2+/NFAT signalling as a novel regulator of nephrogenesis.