Dragatsis I, Efstratiadis A, Zeitlin S
Department of Genetics, Columbia University, New York, NY 10032, USA.
Development. 1998 Apr;125(8):1529-39. doi: 10.1242/dev.125.8.1529.
Mouse embryos nullizygous for a targeted disruption of the Huntington's disease gene homologue (Hdh), which encodes a protein (huntingtin) of unknown biochemical function, become developmentally retarded and disorganized, and die early in development. Using chimeric analysis, we demonstrate that extensively chimeric embryos derived by injection of Hdh null ES cells into wild-type host blastocysts are rescued from lethality. In contrast, when wild-type ES cells are injected into Hdh null blastocysts, the chimeric embryos are morphologically indistinguishable from Hdh null mutants derived from natural matings, and die shortly after gastrulation. Therefore, the primary defect in the absence of huntingtin lies in extraembryonic tissues, whereas the epiblast and its derivatives are affected secondarily. It is likely that the mutation results in impairment of the nutritive functions of the visceral endoderm, which otherwise appears to differentiate normally, as evidenced by the expression of several specific marker genes. Consistent with preliminary histochemical analysis indicating that at least the transport of ferric ions is defective in Hdh mutants and in conjunction with the known localization of huntingtin in the membranes of vesicles associated with microtubules, we hypothesize that this protein is involved in the intracellular trafficking of nutrients in early embryos.
亨廷顿舞蹈病基因同源物（Hdh）的靶向破坏导致纯合缺失的小鼠胚胎，该基因编码一种生化功能未知的蛋白质（亨廷顿蛋白），胚胎发育迟缓且结构紊乱，并在发育早期死亡。通过嵌合体分析，我们证明将Hdh基因敲除的胚胎干细胞注射到野生型宿主囊胚中获得的广泛嵌合胚胎可从致死状态中获救。相反，当将野生型胚胎干细胞注射到Hdh基因敲除的囊胚中时，嵌合胚胎在形态上与自然交配产生的Hdh基因敲除突变体无法区分，并在原肠胚形成后不久死亡。因此，缺乏亨廷顿蛋白时的主要缺陷在于胚外组织，而外胚层及其衍生物则是继发受到影响。突变可能导致脏内胚层营养功能受损，尽管通过几个特定标记基因的表达证明其似乎能正常分化。与初步组织化学分析一致，该分析表明Hdh突变体中至少铁离子的转运存在缺陷，并且结合亨廷顿蛋白在与微管相关的囊泡膜中的已知定位，我们推测该蛋白参与早期胚胎中营养物质的细胞内运输。
