Department of Internal Medicine III, Jena University Hospital, 07747 Jena, Germany.
Medical Physics Group, Institute of Diagnostic and Interventional Radiology, Jena University Hospital, 07747 Jena, Germany.
Biomolecules. 2023 Jun 24;13(7):1037. doi: 10.3390/biom13071037.
The mitogen-activated protein kinase organizer 1 (MORG1) is a scaffold molecule for the ERK signaling pathway, but also binds to prolyl-hydroxylase 3 and modulates HIFα expression. To obtain further insight into the role of MORG1, knockout-mice were generated by homologous recombination. While Morg1+/- mice developed normally without any apparent phenotype, there were no live-born Morg1-/- knockout offspring, indicating embryonic lethality. The intrauterine death of Morg1-/- embryos is caused by a severe failure to develop brain and other neuronal structures such as the spinal cord and a failure of chorioallantoic fusion. On E8.5, Morg1-/- embryos showed severe underdevelopment and proliferative arrest as indicated by absence of Ki67 expression, impaired placental vascularization and altered phenotype of trophoblast giant cells. On E9.5, the malformed Morg1-/- embryos showed defective turning into the final fetal position and widespread apoptosis in many structures. In the subsequent days, apoptosis and decomposition of embryonic tissue progressed, accompanied by a massive infiltration of inflammatory cells. Developmental aberrancies were accompanied by altered expression of HIF-1/2α and VEGF-A and caspase-3 activation in embryos and extraembryonic tissues. In conclusion, the results suggest a multifactorial process that causes embryonic death in homozygous Morg1 mutant mice, described here, to the best of our knowledge, for the first time.
丝裂原活化蛋白激酶组织者 1（MORG1）是 ERK 信号通路的支架分子，但也与脯氨酰羟化酶 3 结合并调节 HIFα 的表达。为了进一步了解 MORG1 的作用，通过同源重组生成了 Morg1 敲除小鼠。虽然 Morg1+/- 小鼠正常发育，没有明显的表型，但没有活产的 Morg1-/- 敲除后代，表明胚胎致死。Morg1-/- 胚胎的宫内死亡是由于大脑和其他神经元结构（如脊髓）严重发育不良以及绒毛膜-卵黄囊融合失败所致。在 E8.5，Morg1-/- 胚胎表现出严重的发育不良和增殖停滞，表现为 Ki67 表达缺失、胎盘血管化受损和滋养层巨细胞表型改变。在 E9.5，畸形的 Morg1-/- 胚胎表现出转向最终胎儿位置的缺陷和许多结构中的广泛细胞凋亡。在随后的几天里，胚胎组织的凋亡和分解进展，伴随着大量炎症细胞的浸润。发育异常伴随着胚胎和胚胎外组织中 HIF-1/2α 和 VEGF-A 的表达改变以及 caspase-3 的激活。总之，这些结果表明，在我们所知的情况下，Morg1 纯合突变小鼠的胚胎死亡是一个多因素的过程。
