Ijpenberg A, Pérez-Pomares J M, Guadix J A, Carmona R, Portillo-Sánchez V, Macías D, Hohenstein P, Miles C M, Hastie N D, Muñoz-Chápuli R
MRC Human Genetics Unit, Western General Hospital, Edinburgh, UK.
Dev Biol. 2007 Dec 1;312(1):157-70. doi: 10.1016/j.ydbio.2007.09.014. Epub 2007 Sep 18.
Previous studies of knock-out mouse embryos have shown that the Wilms' tumor suppressor gene (Wt1) is indispensable for the development of kidneys, gonads, heart, adrenals and spleen. Using OPT (Optical Projection Tomography) we have found a new role for Wt1 in mouse liver development. In the absence of Wt1, the liver is reduced in size, and shows lobing abnormalities. In normal embryos, coelomic cells expressing Wt1, GATA-4, RALDH2 and RXRalpha delaminate from the surface of the liver, intermingle with the hepatoblasts and incorporate to the sinusoidal walls. Some of these cells express desmin, suggesting a contribution to the stellate cell population. Other cells, keeping high levels of RXRalpha immunoreactivity, are negative for stellate or smooth muscle cell markers. However, coelomic cells lining the liver of Wt1-null embryos show decreased or absent RALDH2 expression, the population of cells expressing high levels of RXRalpha is much reduced and the proliferation of hepatoblasts and RXRalpha-positive cells is significantly decreased. On the other hand, the expression of smooth muscle cell specific alpha-actin increases throughout the liver, suggesting an accelerated and probably anomalous differentiation of stellate cell progenitors. We describe a similar retardation of liver growth in RXRalpha-null mice as well as in chick embryos after inhibition of retinoic acid synthesis. We propose that Wt1 expression in cells delaminating from the coelomic epithelium is essential for the expansion of the progenitor population of liver stellate cells and for liver morphogenesis. Mechanistically, at least part of this effect is mediated via the retinoic acid signaling pathway.
先前对基因敲除小鼠胚胎的研究表明，威尔姆斯肿瘤抑制基因（Wt1）对于肾脏、性腺、心脏、肾上腺和脾脏的发育不可或缺。利用光学投影断层扫描（OPT）技术，我们发现了Wt1在小鼠肝脏发育中的新作用。在缺乏Wt1的情况下，肝脏体积减小，并出现叶状异常。在正常胚胎中，表达Wt1、GATA-4、RALDH2和RXRα的体腔细胞从肝脏表面脱层，与成肝细胞混合并整合到窦状壁中。其中一些细胞表达结蛋白，提示对星状细胞群体有贡献。其他细胞保持高水平的RXRα免疫反应性，对星状或平滑肌细胞标志物呈阴性。然而，Wt1基因敲除胚胎肝脏的体腔细胞RALDH2表达降低或缺失，表达高水平RXRα的细胞群体大幅减少，成肝细胞和RXRα阳性细胞的增殖显著降低。另一方面，平滑肌细胞特异性α-肌动蛋白的表达在整个肝脏中增加，提示星状细胞祖细胞的分化加速且可能异常。我们描述了在RXRα基因敲除小鼠以及抑制视黄酸合成后的鸡胚胎中肝脏生长的类似延迟现象。我们提出，从体腔上皮脱层的细胞中Wt1的表达对于肝脏星状细胞祖细胞群体的扩增和肝脏形态发生至关重要。从机制上讲，这种作用至少部分是通过视黄酸信号通路介导的。
