Department of Molecular and Human Genetics, Baylor College of Medicine, One Baylor Plaza MS227, R804, Houston, Texas 77030, USA.
Adv Exp Med Biol. 2010;693:82-92. doi: 10.1007/978-1-4419-7005-3_6.
Functional studies of the mouse quaking gene (Qk) have focused on its role in the postnatal central nervous system during myelination. However, the death of the majority of homozygous mouse quaking alleles revealed that quaking has a critical role in embryonic development prior to the start of myelination. Surprisingly, the lethal alleles revealed that quaking has a function in embryonic blood vessel formation and remodeling. Further studies ofthe extraembryonic yolk sac showed that Qk regulates visceral endoderm differentiated function at the cellular level, including the local synthesis of retinoic acid (RA), which then exerts paracrine control of endothelial cells within adjacent mesoderm. Endoderm-derived RA regulates proliferation of endothelial cells and extracellular matrix (ECM) production, which in a reciprocal manner, modulates visceral endoderm survival and function. Although exogenous RA can rescue endothelial cell growth control and ECM production in mutants carrying a lethal mutation, which lack functional Qk, neither visceral endoderm function nor vascular remodeling is restored. Thus, Qk also regulates cell autonomous functions of visceral endoderm that are critical for vascular remodeling. Interestingly, quaking is highly expressed during normal cardiac development, particularly in the outflow tract, suggesting potentially unique functions in the developing heart. Together, the work on Qk in mammalian embryos reveals an essential, yet under appreciated, role in cardiovascular development. This suggests that certain functions may remain conserved in the early embryo throughout the evolution of nonvertebrate and vertebrate organisms and that additional roles for quaking remain to be discovered.
对小鼠震颤基因（Qk）的功能研究主要集中在髓鞘形成过程中其在出生后中枢神经系统中的作用。然而，大多数纯合 mouse quaking 等位基因的死亡表明，在髓鞘形成之前，Qk 在胚胎发育中起着至关重要的作用。令人惊讶的是，致死等位基因表明 Qk 在胚胎血管形成和重塑中具有功能。对胚胎卵黄囊的进一步研究表明，Qk 在细胞水平上调节内脏内胚层分化功能，包括局部合成视黄酸（RA），然后对相邻中胚层内皮细胞发挥旁分泌控制作用。内胚层衍生的 RA 调节内皮细胞的增殖和细胞外基质（ECM）的产生，而 ECM 的产生以一种互惠的方式调节内脏内胚层的存活和功能。尽管外源性 RA 可以挽救携带致命突变（缺乏功能性 Qk）的突变体中内皮细胞生长控制和 ECM 产生，但既不能恢复内脏内胚层功能，也不能恢复血管重塑。因此，Qk 还调节对血管重塑至关重要的内脏内胚层的细胞自主功能。有趣的是，在正常心脏发育过程中，特别是在流出道中，Qk 高度表达，这表明其在发育中的心脏中可能具有独特的功能。总之，对哺乳动物胚胎中 Qk 的研究揭示了其在心血管发育中具有重要但尚未被充分认识的作用。这表明，在无脊椎动物和脊椎动物生物进化过程中，某些功能在早期胚胎中可能仍然保守，而 Qk 的其他作用仍有待发现。
