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首页> 外文期刊>Proceedings of the National Academy of Sciences of the United States of America >Mutations in mouse Aspm (abnormal spindle-like microcephaly associated) cause not only microcephaly but also major defects in the germline
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Mutations in mouse Aspm (abnormal spindle-like microcephaly associated) cause not only microcephaly but also major defects in the germline

机译：小鼠Aspm突变（异常的纺锤状小头畸形）不仅引起小头畸形，而且还会引起种系的重大缺陷

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摘要

Mutations in ASPM (abnormal spindle-like microcephaly associated) cause primary microcephaly in humans, a disorder characterized by a major reduction in brain size in the apparent absence of nonneurological anomalies. The function of the Aspm protein in neural progenitor cell expansion, as well as its localization to the mitotic spindle and midbody, suggest that it regulates brain development by a cell division-related mechanism. Furthermore, evidence that positive selection affected ASPM during primate evolution has led to suggestions that such a function changed during primate evolution. Here, we report that in Aspm mutant mice, truncated Aspm proteins similar to those causing microcephaly in humans fail to localize to the midbody during M-phase and cause mild microcephaly. A human ASPM transgene rescues this pheno-type but, interestingly, does not cause a gain of function. Strikingly, truncated Aspm proteins also cause a massive loss of germ cells, resulting in a severe reduction in testis and ovary size accompanied by reduced fertility. These germline effects, too, are fully rescued by the human ASPM transgene, indicating that ASPM is functionally similar in mice and humans. Our findings broaden the spectrum of phenotypic effects of ASPM mutations and raise the possibility that positive selection of ASPM during primate evolution reflects its function in the germline.
机译：ASPM（异常的纺锤状小头畸形相关）突变会导致人类原发性小头畸形，这种疾病的特征是在明显缺乏非神经系统异常的情况下脑部大小大幅减少。 Aspm蛋白在神经祖细胞扩增中的功能，以及其定位于有丝分裂纺锤体和中体的功能，表明它通过细胞分裂相关的机制调节大脑的发育。此外，有证据表明阳性选择会在灵长类动物进化过程中影响ASPM，这提示这种功能在灵长类动物进化过程中发生了变化。在这里，我们报告说，在Aspm突变小鼠中，类似于引起人类小头畸形的蛋白质的截短的Aspm蛋白在M期无法定位到中体，并导致轻度小头畸形。人类ASPM转基因可以挽救这种表型，但有趣的是，不会引起功能增强。令人惊讶的是，截短的Aspm蛋白也会引起生殖细胞的大量损失，从而导致睾丸和卵巢大小的严重减少，并伴随着生育力的降低。这些种系效应也被人类ASPM转基因完全拯救，表明ASPM在小鼠和人类中在功能上相似。我们的发现扩大了ASPM突变的表型作用范围，并提高了灵长类动物进化过程中ASPM的阳性选择反映其在种系中的功能的可能性。

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    Jeremy N. Pulvers; Jaroslaw Bryk; Jennifer L. Fish; Michaela Wilsch-Braeuninger; Yoko Arai; Dora Schreier; Ronald Naumann; Jussi Helppi; Bianca Habermann; Johannes Vogt; Robert Nitsch; Attila Toth; Wolfgang Enard; Svante Paeaebo; Wieland B. Huttner;

  • 作者单位

    Max Planck Institute of Molecular Cell Biology and Genetics, 01307 Dresden, Germany RIKEN Center for Developmental Biology, Kobe 650-0047, Japan;

    rnMax Planck Institute for Evolutionary Anthropology, 04103 Leipzig, Germany Max Planck Institute for Evolutionary Biology, 24306 PIon, Germany;

    rnMax Planck Institute of Molecular Cell Biology and Genetics, 01307 Dresden, Germany Department of Craniofacial Development King's College London, Guy's Hospital, SE19RT London, United Kingdom;

    rnMax Planck Institute of Molecular Cell Biology and Genetics, 01307 Dresden, Germany;

    rnMax Planck Institute of Molecular Cell Biology and Genetics, 01307 Dresden, Germany;

    rnMax Planck Institute of Molecular Cell Biology and Genetics, 01307 Dresden, Germany;

    rnMax Planck Institute of Molecular Cell Biology and Genetics, 01307 Dresden, Germany;

    rnMax Planck Institute of Molecular Cell Biology and Genetics, 01307 Dresden, Germany;

    rnMax Planck Institute of Molecular Cell Biology and Genetics, 01307 Dresden, Germany Max Planck Institute for the Biology of Aging, 50931 Cologne, Germany;

    rnInstitute for Cell Biology and Neurobiology, Center for Anatomy, Charite-Universitatsmedizin Berlin, 10115 Berlin, Germany Institute for Microscopic Anatomy and Neurobiology, University Medicine Mainz, Johannes Gutenberg University Mainz, 55131 Mainz, Germany;

    rnInstitute for Cell Biology and Neurobiology, Center for Anatomy, Charite-Universitatsmedizin Berlin, 10115 Berlin, Germany Institute for Microscopic Anatomy and Neurobiology, University Medicine Mainz, Johannes Gutenberg University Mainz, 55131 Mainz, Germany;

    rnlnstitute of Physiological Chemistry, Technische Universitaet Dresden, 01307 Dresden, Germany;

    rnMax Planck Institute for Evolutionary Anthropology, 04103 Leipzig, Germany;

    rnMax Planck Institute for Evolutionary Anthropology, 04103 Leipzig, Germany;

    rnMax Planck Institute of Molecular Cell Biology and Genetics, 01307 Dresden, Germany;

  • 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
  • 中图分类
  • 关键词

    evolution; cerebral cortex; fertility; neural stem cells; germ cells;

    机译：演化;大脑皮层生育能力神经干细胞生殖细胞;

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