MRC Human Genetics Unit, Institute of Genetics & Molecular Medicine, Western General Hospital, Crewe Road, Edinburgh EH4 2XU, UK.
Dev Biol. 2011 Apr 15;352(2):288-98. doi: 10.1016/j.ydbio.2011.01.033. Epub 2011 Feb 3.
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.
许多 Wnt 基因在肾脏早期发育过程中表达，并被认为对其至关重要。通常假设它们的产物将通过经典的β-连环蛋白信号通路发挥作用。我们已经发现证据表明，经典 Wnt 信号通路在早期肾原基的中肾间充质中不活跃，但相反，提供表达和功能证据表明非经典钙/ NFAT Wnt 信号通路在肾发生中起作用。NFAT（T 细胞中激活的核因子）转录因子基因家族的成员在整个鼠肾形态发生过程中表达，NFATc3 定位于发育中的肾单位。用环孢素 A（CSA）处理肾原基，这是一种钙/NFAT 信号通路的抑制剂，会减少肾单位的形成 - 这种表型类似于 Wnt4（-/-）胚胎的表型。用离子霉素处理 Wnt4（-/-）肾脏，这是该途径的激活剂，部分挽救了表型。我们提出，非经典钙/ NFAT Wnt 信号通路在哺乳动物肾脏早期发育中起重要作用，并且在肾发生过程中需要完全的 MET，可能在 Wnt4 下游发挥作用。
