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Intrinsically determined cell death of developing cortical interneurons

机译:本征确定发育中的皮质神经元的细胞死亡

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摘要

Cortical inhibitory circuits are formed by γ-aminobutyric acid (GABA)-secreting interneurons, a cell population that originates far from the cerebral cortex in the embryonic ventral forebrain. Given their distant developmental origins, it is intriguing how the number of cortical interneurons is ultimately determined. One possibility, suggested by the neurotrophic hypothesis, is that cortical interneurons are overproduced, and then after their migration into cortex the excess interneurons are eliminated through a competition for extrinsically derived trophic signals. Here we characterize the developmental cell death of mouse cortical interneurons in vivo, in vitro and after transplantation. We found that 40% of developing cortical interneurons were eliminated through Bax (Bcl-2-associated X)-dependent apoptosis during postnatal life. When cultured in vitro or transplanted into the cortex, inter-neuron precursors died at a cellular age similar to that at which endogenous interneurons died during normal development. Over transplant sizes that varied 200-fold, a constant fraction of the transplanted population underwent cell death. The death of transplanted neurons was not affected by the cell-autonomous disruption of TrkB (tropomyosin kinase receptor B), the main neurotrophin receptor expressed by neurons of the central nervous system. Transplantation expanded the cortical interneuron population by up to 35%, but the frequency of inhibitory synaptic events did not scale with the number of transplanted interneurons. Taken together, our findings indicate that interneuron cell death is determined intrinsically, either cell-autonomously or through a population-autonomous competition for survival signals derived from other interneurons.
机译:皮质抑制回路是由分泌γ-氨基丁酸(GABA)的中间神经元形成的,该神经元是一种细胞群,起源于胚胎腹侧前脑的大脑皮层。鉴于它们的遥远的起源,令人着迷的是如何最终确定皮层中间神经元的数量。神经营养假说提出的一种可能性是,皮质神经元被过度生产,然后在它们迁移到皮质后,通过竞争外源性营养信号消除了多余的神经元。在这里,我们表征体内,体外和移植后小鼠皮层interneurons的发育细胞死亡。我们发现,在出生后的生命中,通过Bax(Bcl-2关联的X)依赖性细胞凋亡消除了发育中的皮质中间神经元。当在体外培养或移植到皮层中时,神经元间前体在与正常发育过程中内源性神经元死亡相似的细胞年龄死亡。超过200倍的移植大小,恒定比例的移植人群经历了细胞死亡。移植的神经元的死亡不受TrkB(原肌球蛋白激酶受体B)的细胞自主破坏的影响,TrkB是中枢神经系统神经元表达的主要神经营养蛋白受体。移植使皮质神经元的数量最多增加了35%,但抑制性突触事件的频率却与移植神经元的数量无关。综上所述,我们的发现表明,中间神经元细胞死亡是内在决定的,细胞自主地决定还是通过群体自主竞争来竞争其他中间神经元的存活信号。

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  • 来源
    《Nature》 |2012年第7422期|p.109-113|共5页
  • 作者单位

    Neuroscience Graduate Program, University of California, San Francisco, California 94143, USA,Departments of Neuroscience and Neurosurgery, and the Eli and Edythe Broad Center of Regeneration Medicine and Stem Cell Research University of California, San Francisco, California 94143, USA,Medical Scientist Training Program, University of California, San Francisco, California 94143, USA Department of Neurosurgery, Stanford University School of Medicine, Stanford, California 94305, USA;

    Departments of Neuroscience and Neurosurgery, and the Eli and Edythe Broad Center of Regeneration Medicine and Stem Cell Research University of California, San Francisco, California 94143, USA,Department of Neurology, University of California, San Francisco, California 94143, USA;

    Departments of Neuroscience and Neurosurgery, and the Eli and Edythe Broad Center of Regeneration Medicine and Stem Cell Research University of California, San Francisco, California 94143, USA Department of Molecular Biology, University of Oregon, Eugene, Oregon 97403, USA;

    Neuroscience Graduate Program, University of California, San Francisco, California 94143, USA,Departments of Neuroscience and Neurosurgery, and the Eli and Edythe Broad Center of Regeneration Medicine and Stem Cell Research University of California, San Francisco, California 94143, USA;

    Department of Otolaryngology, Coleman Memorial Laboratory and W.M. Keck Foundation Center for Integrative Neuroscience, University of California, San Francisco, California 94143, USA Molecular Neurobiology Program, The Helen and Martin Kimmel Center for Biology and Medicine at the Skirball Institute of Biomolecular Medicine, DepartmentsofOtolaryngology, Physiology and Neuroscience, New York University School of Medicine, New York, New York 10016, USA;

    Departments of Neuroscience and Neurosurgery, and the Eli and Edythe Broad Center of Regeneration Medicine and Stem Cell Research University of California, San Francisco, California 94143, USA;

    Instituto Cavanilles, Universidad de Valencia, CIBERNED, Valencia 46071, Spain Cambridge Centre for Brain Repair, Department of Clinical Neurosciences and Stem Cell Institute, University of Cambridge, Cambridge CB2 0PY, UK;

    Departments of Neuroscience and Neurosurgery, and the Eli and Edythe Broad Center of Regeneration Medicine and Stem Cell Research University of California, San Francisco, California 94143, USA,Medical Scientist Training Program, University of California, San Francisco, California 94143, USA,Biomedical Sciences Graduate Program, University of California, San Francisco, California 94143, USA;

    Instituto Cavanilles, Universidad de Valencia, CIBERNED, Valencia 46071, Spain;

    Department of Psychiatry and the Eli and Edythe Broad Center of Regeneration Medicine and Stem Cell Research, University of California, San Francisco, California 94143, USA;

    Neuroscience Graduate Program, University of California, San Francisco, California 94143, USA,Departments of Neuroscience and Neurosurgery, and the Eli and Edythe Broad Center of Regeneration Medicine and Stem Cell Research University of California, San Francisco, California 94143, USA;

    Neuroscience Graduate Program, University of California, San Francisco, California 94143, USA,Departments of Neuroscience and Neurosurgery, and the Eli and Edythe Broad Center of Regeneration Medicine and Stem Cell Research University of California, San Francisco, California 94143, USA;

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