We have developed yeast artificial chromosome (YAC) transgenic mice expressing normal (YAC18) and mutant (YAC46 or YAC72) human huntingtin (htt), in a developmental- and tissue-specific manner, that is identical to endogenous htt. YAC72 mice develop selective degeneration of medium spiny projection neurons in the lateral striatum, similar to what is observed in Huntington disease. Mutant human htt expressed by YAC transgenes can compensate for the absence of endogenous htt and can rescue the embryonic lethality that characterizes mice homozygous for targeted disruption of the endogenous Hdh gene (-/-). YAC72 mice lacking endogenous htt (YAC72 -/-) manifest a novel phenotype characterized by infertility, testicular atrophy, aspermia, and massive apoptotic cell death in the testes. The testicular cell death in YAC72 -/- mice can be markedly reduced by increasing endogenous htt levels. YAC72 mice with equivalent levels of both wild-type and mutant htt (YAC72 +/+) breed normally and have no evidence of increased testicular cell death. Similar findings are seen in YAC46 -/- mice compared with YAC46 +/+ mice, in which wild-type htt can completely counteract the proapoptotic effects of mutant htt. YAC18 -/- mice display no evidence of increased cellular apoptosis, even in the complete absence of endogenous htt, demonstrating that the massive cellular apoptosis observed in YAC46 -/- mice and YAC72 -/- mice is polyglutamine-mediated toxicity from the mutant transgene. These data provide the first direct in vivo evidence of a role for wild-type htt in decreasing the cellular toxicity of mutant htt.

中文翻译：

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野生型亨廷顿蛋白降低了体内突变亨廷顿蛋白的细胞毒性。

我们已经开发出以发育和组织特异性方式表达正常（YAC18）和突变体（YAC46或YAC72）人类亨廷顿蛋白（htt）的酵母人工染色体（YAC）转基因小鼠，与内源性htt相同。YAC72小鼠在外侧纹状体中发展出中性多刺投射神经元的选择性变性，类似于在亨廷顿病中观察到的情况。由YAC转基因表达的突变型人htt可以补偿内源性htt的缺失，并可以挽救以小鼠为内源性Hdh基因（-/-）定向纯合子的胚胎致死性。缺乏内源性HTT（YAC72-/-）的YAC72小鼠表现出一种新的表型，其特征为不育，睾丸萎缩，无精子症和睾丸中大量的凋亡细胞死亡。通过增加内源性htt水平，可以显着降低YAC72-/-小鼠的睾丸细胞死亡。具有相同水平的野生型和突变型htt（YAC72 + / +）的YAC72小鼠正常繁殖，并且没有睾丸细胞死亡增加的证据。与YAC46 + / +小鼠相比，在YAC46-/-小鼠中观察到类似的发现，其中野生型htt可以完全抵消突变型htt的促凋亡作用。YAC18-/-小鼠甚至在完全不存在内源性htt的情况下也没有显示出细胞凋亡增加的证据，这表明在YAC46-/-小鼠和YAC72-/-小鼠中观察到的大量细胞凋亡是多聚谷氨酰胺介导的突变转基因毒性。这些数据提供了野生型htt在降低突变型htt的细胞毒性中的作用的第一个直接的体内证据。具有相同水平的野生型和突变型htt（YAC72 + / +）的YAC72小鼠正常繁殖，并且没有睾丸细胞死亡增加的证据。与YAC46 + / +小鼠相比，在YAC46-/-小鼠中观察到类似的发现，其中野生型htt可以完全抵消突变型htt的促凋亡作用。YAC18-/-小鼠甚至在完全不存在内源性htt的情况下也没有显示出细胞凋亡增加的证据，这表明在YAC46-/-小鼠和YAC72-/-小鼠中观察到的大量细胞凋亡是多聚谷氨酰胺介导的突变转基因毒性。这些数据提供了野生型htt在降低突变型htt的细胞毒性中的作用的第一个直接的体内证据。具有相同水平的野生型和突变型htt（YAC72 + / +）的YAC72小鼠正常繁殖，并且没有睾丸细胞死亡增加的证据。与YAC46 + / +小鼠相比，在YAC46-/-小鼠中观察到类似的发现，其中野生型htt可以完全抵消突变型htt的促凋亡作用。YAC18-/-小鼠甚至在完全不存在内源性htt的情况下也没有显示出细胞凋亡增加的证据，这表明在YAC46-/-小鼠和YAC72-/-小鼠中观察到的大规模细胞凋亡是多聚谷氨酰胺介导的突变转基因毒性。这些数据提供了野生型htt在降低突变型htt的细胞毒性中的作用的第一个直接的体内证据。