New evidence confirms that the mitochondrial bottleneck is generated without reduction of mitochondrial DNA content in early primordial germ cells of mice.
New evidence confirms that the mitochondrial bottleneck is generated without reduction of mitochondrial DNA content in early primordial germ cells of mice.
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DOI：
10.1371/journal.pgen.1000756
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发表时间：
2009-12
期刊：
影响因子：
4.5
通讯作者：
Yonekawa H
中科院分区：
文献类型：
--
作者：
Cao L;Shitara H;Sugimoto M;Hayashi J;Abe K;Yonekawa H
在哺乳动物中，观察到线粒体DNA（mtDNA）变异在世代之间的快速变化，导致了mtDNA传播的瓶颈理论的建立。瓶颈可能归因于生殖细胞中线粒体DNA含量的显着下降，从而产生下一代，归因于同质类核而不是单个线粒体DNA分子作为分离单位产生的少量有效线粒体DNA分离单位，或者归因于选择性传递线粒体DNA群体的亚群到后代。我们先前已经确定了单个生殖细胞中mtDNA的拷贝数，并表明在生殖细胞mtDNA含量没有减少的情况下出现瓶颈。最近的一项研究表明，瓶颈是由早期原始生殖细胞（PGC）中mtDNA拷贝的显着下降驱动的，而另一项研究报告，mtDNA遗传瓶颈是由出生后卵母细胞成熟过程中mtDNA基因组亚群的复制而不是在胚胎卵子发生过程中引起的，尽管在早期PGC中检测到mtDNA含量减少。为了澄清这些相互矛盾的结果，我们检查了从转基因小鼠中分离的PGCs中的mtDNA拷贝数，所述转基因小鼠在PGCs中特异性表达荧光蛋白，如在上述另外两个研究中一样。我们提供了明确的证据，以确认没有显着减少的mtDNA含量发生在PGCs和加强的瓶颈是产生没有减少的mtDNA含量在生殖细胞。线粒体DNA的突变是人类许多类型线粒体疾病的原因，包括肌病和神经系统疾病。携带突变型和野生型mtDNA变体混合物的雌性将可变数量的突变型mtDNA传递给每个后代。遗传自母亲的突变mtDNA的比例决定了疾病的发作和严重程度。研究表明，mtDNA基因组是通过瓶颈传递的，但其潜在机制仍存在争议。通过检测单细胞中mtDNA的拷贝数，我们先前表明，在生殖细胞中mtDNA含量没有减少的情况下，瓶颈发生。然而，最近的一项研究报告了胚胎生殖细胞中mtDNA拷贝的显着下降，并将这种减少归因于瓶颈的产生。另一项研究得出结论，瓶颈发生在出生后卵母细胞成熟期间，而不是在胚胎卵子发生期间。为了解决这些争议，我们使用与其他两项研究相同的方法检测了胚胎生殖细胞中的mtDNA拷贝。我们提供了确凿的证据来证实我们以前的发现。这一确认是重要的，因为女性生殖细胞中mtDNA含量的了解将有助于预防线粒体疾病从母亲传播给后代的治疗策略的发展。
In mammals, observations of rapid shifts in mitochondrial DNA (mtDNA) variants between generations have led to the creation of the bottleneck theory for the transmission of mtDNA. The bottleneck could be attributed to a marked decline of mtDNA content in germ cells giving rise to the next generation, to a small effective number of mtDNA segregation units resulting from homoplasmic nucleoids rather than the single mtDNA molecule serving as the units of segregation, or to the selective transmission of a subgroup of the mtDNA population to the progeny. We have previously determined mtDNA copy number in single germ cells and shown that the bottleneck occurs without the reduction in germline mtDNA content. Recently one study suggested that the bottleneck is driven by a remarkable decline of mtDNA copies in early primordial germ cells (PGCs), while another study reported that the mtDNA genetic bottleneck results from replication of a subpopulation of the mtDNA genome during postnatal oocyte maturation and not during embryonic oogenesis, despite a detected a reduction in mtDNA content in early PGCs. To clarify these contradictory results, we examined the mtDNA copy number in PGCs isolated from transgenic mice expressing fluorescent proteins specifically in PGCs as in the aforementioned two other studies. We provide clear evidence to confirm that no remarkable reduction in mtDNA content occurs in PGCs and reinforce that the bottleneck is generated without reduction of mtDNA content in germ cells. Mutations of mtDNA are responsible for many types of mitochondrial diseases in humans, including myopathy and neurological disorders. Females carrying a mixture of mutant and wild-type mtDNA variants transmit a variable amount of mutant mtDNA to each offspring. The proportion of mutated mtDNA inherited from the mother determines the onset and severity of diseases. Studies have suggested that the mtDNA genome is transmitted through a bottleneck, but the underlying mechanism remains controversial. By detecting mtDNA copy number in single cells, we previously showed that the bottleneck occurs without reduction of mtDNA content in germline cells. However, recently a study reported a marked decline of mtDNA copies in embryonic germ cells and attributed this reduction to the creation of the bottleneck. Yet another study concluded that the bottleneck occurs during postnatal oocyte maturation and not during embryonic oogenesis. To resolve these controversies, we examined mtDNA copies in embryonic germ cells identified using the same methodology as in the other two studies. We show solid evidence to confirm our previous findings. This confirmation is important because the understanding of mtDNA content in female germ cells will facilitate the development of therapeutic strategies preventing the transmission of mitochondrial diseases from mother to offspring.
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