HP1γ function is required for male germ cell survival and spermatogenesis
HP1γ function is required for male germ cell survival and spermatogenesis
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DOI：
10.1186/1756-8935-3-9
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发表时间：
2010-04-27
影响因子：
3.9
通讯作者：
Singh, Prim B.
中科院分区：
文献类型：
--
作者：
Brown, Jeremy P.;Bullwinkel, Joern;Singh, Prim B.
背景：HP1蛋白是真核生物组成异染色质的保守成分。在哺乳动物中，有三个基因编码HP1样蛋白，分别是HP1 α、HP1 β和HP1 γ，它们具有高度的同源性。本文首次用基因靶向小鼠描述了HP1 γ的生理功能。结果：利用条件靶向载体靶向Cbx3基因（编码HP1 γ蛋白），我们产生了一个次胚等位基因（Cbx3(hypo)），导致HP1 γ蛋白水平大大降低（几乎无法检测到）。次型等位基因（Cbx3(hypo/hypo)）的纯合子很少见，只有1%的Cbx3（hypo/hypo）动物能达到成年期。成年雄性表现出严重的性腺功能减退，这与生殖细胞的丧失有关，一些精小管只保留了支持的支持细胞（仅支持细胞表型）。Cbx3（hypoo / hypoo）睾丸中L1 ORF1蛋白（ORF1p）阳性的精管比例大于野生型睾丸，表明L1反转录转座子沉默被逆转，导致ORF1p在Cbx3（hypoo / hypoo）生殖细胞中异位表达。结论：Cbx3基因产物（HP1 γ蛋白）在精子发生过程中具有非冗余功能，这是其他两种HP1同型基因无法弥补的。Cbx3（低/低）精子发生缺陷与Miwi2和Dnmt3L突变体相似。本研究构建的Cbx3基因靶向小鼠为HP1 γ在转座子沉默和亲代印记中的研究提供了合适的模型。
Background: HP1 proteins are conserved components of eukaryotic constitutive heterochromatin. In mammals, there are three genes that encode HP1-like proteins, termed HP1 alpha, HP1 beta and HP1 gamma, which have a high degree of homology This paper describes for the first time, to our knowledge, the physiological function of HP1 gamma using a gene-targeted mouse.Results: While targeting the Cbx3 gene (encoding the HP1 gamma protein) with a conditional targeting vector, we generated a hypomorphic allele (Cbx3(hypo)), which resulted in much reduced (barely detectable) levels of HP1 gamma protein. Homozygotes for the hypomorphic allele (Cbx3(hypo/hypo)) are rare, with only 1% of Cbx3(hypo/hypo) animals reaching adulthood. Adult males exhibit a severe hypogonadism that is associated with a loss of germ cells, with some seminiferous tubules retaining only the supporting Sertoli cells (Sertoli cell-only phenotype). The percentage of seminiferous tubules that are positive for L1 ORF1 protein (ORF1p) in Cbx3(hypo/hypo) testes is greater than that for wildtype testes, indicating that L1 retrotransposon silencing is reversed, leading to ectopic expression of ORF1p in Cbx3(hypo/hypo) germ cells.Conclusions: The Cbx3 gene product (the HP1 gamma protein) has a non-redundant function during spermatogenesis that cannot be compensated for by the other two HP1 isotypes. The Cbx3(hypo/hypo) spermatogenesis defect is similar to that found in Miwi2 and Dnmt3L mutants. The Cbx3 gene-targeted mice generated in this study provide an appropriate model for the study of HP1 gamma in transposon silencing and parental imprinting.