Wt1 and retinoic acid signaling are essential for stellate cell development and liver morphogenesis

• Published in: Developmental biology 2007-12, Vol.312 (1), p.157-170
• Main Authors: 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.
• Format: Article
• Language: English
• Subjects: Aldehyde Oxidoreductases - antagonists & inhibitors; Animals; Biomarkers - metabolism; Cell Differentiation - drug effects; Cell Proliferation - drug effects; Chick Embryo; Embryo, Mammalian - cytology; Embryo, Mammalian - drug effects; Hepatocytes - cytology; Hepatocytes - drug effects; Hepatocytes - enzymology; Liver - drug effects; Liver - embryology; Liver - enzymology; Liver - pathology; Liver development; Mice; Mice, Knockout; Models, Biological; Monoterpenes - pharmacology; Morphogenesis - drug effects; Phenotype; Quail; RALDH2; Retinoic acid; Retinoid X Receptor alpha - metabolism; RXRα; Signal Transduction - drug effects; Stellate cells; Stomach - anatomy & histology; Stomach - drug effects; Tretinoin - pharmacology; Wt1; WT1 Proteins - deficiency; WT1 Proteins - metabolism
• ISSN: 0012-1606; 1095-564X
• DOI: 10.1016/j.ydbio.2007.09.014

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 RXRα 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 RXRα 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 RXRα is much reduced and the proliferation of hepatoblasts and RXRα-positive cells is significantly decreased. On the other hand, the expression of smooth muscle cell specific α-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 RXRα-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.