Development and initial characterization of xenomitochondrial mice.
Development and initial characterization of xenomitochondrial mice.
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异线粒体小鼠的发育和初步表征。
DOI：
10.1023/b:jobb.0000041778.84464.16
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发表时间：
2004
影响因子：
3
通讯作者：
Pinkert,CA
中科院分区：
文献类型：
--
作者：
Trounce,IA;McKenzie,M;Cassar,CA;Ingraham,CA;Lerner,CA;Dunn,DA;Donegan,CL;Takeda,K;Pogozelski,WK;Howell,RL;Pinkert,CA
在家鼠（aMus musus domesticus， MD）核背景下培育了携带跨种线粒体的异线粒体小鼠。我们通过融合Mus spretus（MS）、Mus caroli（MC）、Mus dunni（Mdu）、Mus pahari（MP）线粒体供体细胞质和罗丹明6-G处理的CC9.3.1或PC4 ES细胞，制备了异种线粒体ES细胞杂交体。所选择的供体背景反映了与MD小鼠的进化差异日益增加，由此产生的线粒体-核错配针对的是分级呼吸链缺陷。将同质（MS、MC、Mdu和MP）和异质（MC）细胞系注射到MD卵中，获得了87只MS/MD 18、46只MC/MD 6、140只Mdu/MD 31和9只MP/MD 1的嵌合小鼠。7只MS/MD、1只MC/MD和11只Mdu/MD嵌合雌性与野生型MD雄性交配，其中18只（95%）可育。在可育雌性中，只有1只嵌合MS/MD（毛色嵌合率为1%）和4只嵌合Mdu/MD（毛色嵌合率为80-90%）产生了低效率的同质后代（7 / 135;5%）。引进线粒体背景的4个雄性和3个雌性后代是同质的。三个雄性和一个雌性的后代被证明是可以存活的。使用额外的雌性胚胎干细胞谱系生成小鼠系正在进行中。我们假设，当这些小鼠与神经退行性疾病小鼠模型杂交时，将显示出与年龄相关的神经元丢失加速，因为它们的氧化磷酸化能力不理想，并且推定氧化应激增加。
Xenomitochondrial mice harboring trans-species mitochondria on aMus musculus domesticus(MD) nuclear background were produced. We created xenomitochondrial ES cell cybrids by fusingMus spretus(MS),Mus caroli(MC),Mus dunni(Mdu), orMus pahari(MP) mitochondrial donor cytoplasts and rhodamine 6-G treated CC9.3.1 or PC4 ES cells. The selected donor backgrounds reflected increasing evolutionary divergence from MD mice and the resultant mitochondrial–nuclear mismatch targeted a graded respiratory chain defect. Homoplasmic (MS, MC, Mdu, and MP) and heteroplasmic (MC) cell lines were injected into MD ova, and liveborn chimeric mice were obtained (MS/MD 18 of 87, MC/MD 6 of 46, Mdu/MD 31 of 140, and MP/MD l of 9 founder chimeras, respectively). Seven MS/MD, 1 MC/MD, and 11 Mdu/MD chimeric founder females were mated with wild-type MD males, and 18 of 19 (95%) were fertile. Of fertile females, only one chimeric MS/MD (1% coat color chimerism) and four chimeric Mdu/MD females (80–90% coat color chimerism) produced homoplasmic offspring with low efficiency (7 of 135; 5%). Four male and three female offspring were homoplasmic for the introduced mitochondrial backgrounds. Three male and one female offspring proved viable. Generation of mouse lines using additional female ES cell lineages is underway. We hypothesize that these mice, when crossbred with neurodegenerative-disease mouse models, will show accelerated age-related neuronal loss, because of their suboptimal capacity for oxidative phosphorylation and putatively increased oxidative stress.