Purkinje cell-specific males absent on the first (mMof) gene deletion results in an ataxia-telangiectasia-like neurological phenotype and backward walking in mice

Rakesh Kumar; Clayton R. Hunt; Arun Gupta; Suraj Nannepaga; Raj K. Pandita; Jerry W. Shay; Robert Bachoo; Thomas Ludwig; Dennis K. Burns; Tej K. Pandita

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Purkinje cell-specific males absent on the first (mMof) gene deletion results in an ataxia-telangiectasia-like neurological phenotype and backward walking in mice

机译：缺乏第一个（mMof）基因缺失的Purkinje细胞特异性雄性导致共济失调-毛细血管扩张样神经表型和小鼠向后行走

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The brains of ataxia telangiectasia (AT) patients display an aberrant loss of Purkinje cells (PCs) that is postulated to contribute to the observed deficits in motor coordination as well as in learning and cognitive function. AT patients have mutations in the ataxia telangiectasia mutated (ATM) gene [Savitsky et al. (1995) Science 268:1749-1753]. However, in Atm-deficient mice, the neurological defects are limited, and the PCs are not deformed or lost as observed in AT patients [Barlow et al. (1996) Cell 86:159-171]. Here we report that PC-specific deletion of the mouse males absent on the first (mMof) gene (Cre~-), which encodes a protein that specifically acetylates histone H4 at lysine 16 (H4K16ac) and influences ATM function, is critical for PC longevity. Mice deficient for PC-specific Mof display impaired motor coordination, ataxia, a backward-walking phenotype, and a reduced life span. Treatment of Mof~(F/F)/Pcp2-Cre~+ mice with histone deacetylase inhibitors modestly prolongs PC survival and delays death. Therefore, Mof expression and H4K16 acetylation are essential for PC survival and function, and their absence leads to PC loss and cerebellar dysfunction similar to that observed in AT patients.

机译：共济失调毛细血管扩张症（AT）患者的大脑显示出Purkinje细胞（PCs）异常丢失，据推测这是造成观察到的运动协调以及学习和认知功能缺陷的原因。 AT患者的共济失调性毛细血管扩张突变（ATM）基因中有突变[Savitsky等。（1995）Science 268：1749-1753]。然而，在Atm缺乏的小鼠中，神经系统的缺陷是有限的，并且PC不会像在AT患者中观察到的那样变形或丢失[Barlow等。（1996）Cell 86：159-171]。在这里，我们报道第一个（mMof）基因（Cre〜-）缺失的小鼠雄性小鼠的PC特异性缺失，该基因编码一种在赖氨酸16（H4K16ac）上特异性乙酰化组蛋白H4并影响ATM功能的蛋白质，对PC至关重要长寿。缺乏PC专用Mof的小鼠显示出运动协调障碍，共济失调，向后移动的表型，以及寿命缩短。用组蛋白脱乙酰基酶抑制剂治疗Mof〜（F / F）/ Pcp2-Cre〜+小鼠可适度延长PC存活时间并延迟死亡。因此，Mof表达和H4K16乙酰化对于PC的生存和功能至关重要，而它们的缺失会导致PC丢失和小脑功能障碍，与AT患者相似。

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《Proceedings of the National Academy of Sciences of the United States of America》 |2011年第9期|p.3636-3641|共6页
作者
Rakesh Kumar; Clayton R. Hunt; Arun Gupta; Suraj Nannepaga; Raj K. Pandita; Jerry W. Shay; Robert Bachoo; Thomas Ludwig; Dennis K. Burns; Tej K. Pandita;
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作者单位

Departments of Radiation Oncology, University of Texas Southwestern Medical Center, Dallas, TX 75390 Department of Radiation Oncology, Washington University School of Medicine, St. Louis, MO 63108;

Departments of Radiation Oncology, University of Texas Southwestern Medical Center, Dallas, TX 75390 Department of Radiation Oncology, Washington University School of Medicine, St. Louis, MO 63108;

Departments of Radiation Oncology, University of Texas Southwestern Medical Center, Dallas, TX 75390 Department of Radiation Oncology, Washington University School of Medicine, St. Louis, MO 63108;

Departments of Neurology, University of Texas Southwestern Medical Center, Dallas, TX 75390;

Department of Radiation Oncology, Washington University School of Medicine, St. Louis, MO 63108 Departments of Cell Biology, University of Texas Southwestern Medical Center, Dallas, TX 75390;

Departments of Cell Biology, University of Texas Southwestern Medical Center, Dallas, TX 75390;

Departments of Neurology, University of Texas Southwestern Medical Center, Dallas, TX 75390;

Institute for Cancer Genetics, Columbia University, New York, NY 10032;

Departments of Pathology, University of Texas Southwestern Medical Center, Dallas, TX 75390;

Departments of Radiation Oncology, University of Texas Southwestern Medical Center, Dallas, TX 75390 Department of Radiation Oncology, Washington University School of Medicine, St. Louis, MO 63108;

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收录信息美国《科学引文索引》(SCI);美国《生物学医学文摘》(MEDLINE);美国《化学文摘》(CA);
原文格式 PDF
正文语种 eng
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关键词
ataxia telangiectasia phenotype; chromatin modification; DNA damage response;

机译：共济失调毛细血管扩张表型;染色质修饰DNA损伤反应;

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6. Purkinje cell-specific males absent on the first (mMof) gene deletion results in an ataxia-telangiectasia-like neurological phenotype and backward walking in mice [O] . Rakesh Kumar, Clayton R. Hunt, Arun Gupta, 2011

机译：缺少第一个（mMof）基因缺失的Purkinje细胞特异性雄性导致小鼠共济失调-毛细血管扩张样神经表型并在小鼠中向后行走
7. Purkinje cell-specific males absent on the first (mMof) gene deletion results in an ataxia-telangiectasia-like neurological phenotype and backward walking in mice [O] . Kumar, Rakesh, Hunt, Clayton R., Gupta, Arun, 2011

机译：缺少第一个（mMof）基因缺失的Purkinje细胞特异性雄性会导致共济失调-毛细血管扩张样神经表型并在小鼠中向后行走

Purkinje cell-specific males absent on the first (mMof) gene deletion results in an ataxia-telangiectasia-like neurological phenotype and backward walking in mice

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