Department of Applied Biological Chemistry, Graduate School of Agricultural and Life Sciences, The University of Tokyo, Bunkyo-ku, Tokyo, Japan.
PLoS One. 2012;7(3):e32991. doi: 10.1371/journal.pone.0032991. Epub 2012 Mar 8.
During mouse embryogenesis, proper formation of the heart and liver is especially important and is crucial for embryonic viability. In this study, we showed that Mab21l2 was expressed in the trabecular and compact myocardium, and that deletion of Mab21l2 resulted in a reduction of the trabecular myocardium and thinning of the compact myocardium. Mab21l2-deficient embryonic hearts had decreased expression of genes that regulate cell proliferation and apoptosis of cardiomyocytes. These results show that Mab21l2 functions during heart development by regulating the expression of such genes. Mab21l2 was also expressed in the septum transversum mesenchyme (STM). Epicardial progenitor cells are localized to the anterior surface of the STM (proepicardium), and proepicardial cells migrate onto the surface of the heart and form the epicardium, which plays an important role in heart development. The rest of the STM is essential for the growth and survival of hepatoblasts, which are bipotential progenitors for hepatocytes and cholangiocytes. Proepicardial cells in Mab21l2-deficient embryos had defects in cell proliferation, which led to a small proepicardium, in which α4 integrin expression, which is essential for the migration of proepicardial cells, was down-regulated, suggesting that defects occurred in its migration. In Mab21l2-deficient embryos, epicardial formation was defective, suggesting that Mab21l2 plays important roles in epicardial formation through the regulation of the cell proliferation of proepicardial cells and the migratory process of proepicardial cells. Mab21l2-deficient embryos also exhibited hypoplasia of the STM surrounding hepatoblasts and decreased hepatoblast proliferation with a resultant loss of defective morphogenesis of the liver. These findings demonstrate that Mab21l2 plays a crucial role in both heart and liver development through STM formation.
在小鼠胚胎发生过程中，心脏和肝脏的正常形成尤为重要，对胚胎的存活至关重要。在这项研究中，我们表明 Mab21l2 在小梁和致密心肌中表达，并且 Mab21l2 的缺失导致小梁心肌减少和致密心肌变薄。Mab21l2 缺陷型胚胎心脏中调节心肌细胞增殖和凋亡的基因表达减少。这些结果表明，Mab21l2 通过调节这些基因的表达在心脏发育过程中发挥作用。Mab21l2 也在横隔系膜间质（STM）中表达。心外膜祖细胞定位于 STM 的前表面（心外膜），心外膜细胞迁移到心脏表面并形成心外膜，在心发育中起重要作用。剩余的 STM 对于肝母细胞的生长和存活至关重要，肝母细胞是肝细胞和胆管细胞的双潜能祖细胞。Mab21l2 缺陷型胚胎中的心外膜祖细胞增殖缺陷，导致心外膜小，α4 整合素表达下调，α4 整合素对心外膜细胞迁移至关重要，提示其迁移发生缺陷。在 Mab21l2 缺陷型胚胎中，心外膜形成缺陷，提示 Mab21l2 通过调节心外膜祖细胞的增殖和心外膜祖细胞的迁移过程在心外膜形成中发挥重要作用。Mab21l2 缺陷型胚胎的 STM 也表现出围绕肝母细胞的发育不良和肝母细胞增殖减少，导致肝脏形态发生缺陷。这些发现表明 Mab21l2 通过 STM 形成在心和肝发育中都发挥着关键作用。
