Noveroske Janice K, Lai Lihua, Gaussin Vinciane, Northrop Jennifer L, Nakamura Hisashi, Hirschi Karen K, Justice Monica J
Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, Texas, USA.
Genesis. 2002 Mar;32(3):218-30. doi: 10.1002/gene.10060.
For nearly 40 years functional studies of the mouse quaking gene (qkI) have focused on its role in the postnatal central nervous system during myelination. However, the homozygous lethality of a number of ENU-induced alleles reveals that quaking has a critical role in embryonic development prior to the start of myelination. In this article, we show that quaking has a previously unsuspected and essential role in blood vessel development. Interestingly, we found that quaking, a nonsecreted protein, is expressed in the yolk sac endoderm, adjacent to the mesodermal site of developing blood islands, where the differentiation of blood and endothelial cells first occurs. Antibodies against PE-CAM-1, TIE-2 and SM-alpha-actin reveal that embryos homozygous for the qk(k2) allele have defective yolk sac vascular remodeling and abnormal vessels in the embryo proper at midgestation, coinciding with the timing of embryonic death. However, these mutants exhibit normal expression of Nkx2.5 and alpha-sarcomeric actin, indicating that cardiac muscle differentiation was normal. Further, they had normal embryonic heart rates in culture, suggesting that cardiac function was not compromised at this stage of embryonic development. Together, these results suggest that quaking plays an essential role in vascular development and that the blood vessel defects are the cause of embryonic death.
近40年来，对小鼠震颤基因（qkI）的功能研究主要集中在其在出生后中枢神经系统髓鞘形成过程中的作用。然而，许多ENU诱导等位基因的纯合致死性表明，震颤在髓鞘形成开始之前的胚胎发育中起关键作用。在本文中，我们表明震颤在血管发育中具有先前未被怀疑的重要作用。有趣的是，我们发现震颤这种非分泌蛋白在卵黄囊内胚层表达，该部位与发育中血岛的中胚层部位相邻，而血岛正是血液和内皮细胞首次分化的地方。针对PE-CAM-1、TIE-2和SM-α-肌动蛋白的抗体显示，qk(k2)等位基因纯合的胚胎在妊娠中期卵黄囊血管重塑存在缺陷，胚胎本身血管异常，这与胚胎死亡时间一致。然而，这些突变体Nkx2.5和α-肌节肌动蛋白表达正常，表明心肌分化正常。此外，它们在培养中的胚胎心率正常，表明在胚胎发育的这个阶段心脏功能未受影响。总之，这些结果表明震颤在血管发育中起重要作用，血管缺陷是胚胎死亡的原因。
