Epistatic and independent functions of Caspase-3 and Bcl-XL in developmental programmed cell death
Epistatic and independent functions of Caspase-3 and Bcl-XL in developmental programmed cell death
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DOI：
10.1073/pnas.97.1.466
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发表时间：
2000-01-04
影响因子：
11.1
通讯作者：
Rakic, P
中科院分区：
文献类型：
--
作者：
Roth, KA;Kuan, CY;Rakic, P
哺乳动物大脑中神经元的数量由细胞增殖和程序性细胞死亡之间的平衡决定。最近的研究表明，Bcl-X-L防止，而Caspase-3介导，在发育中的神经系统中的细胞死亡，但是否Bcl-X-L直接阻断Caspase-3在体内的凋亡功能是未知的。去研究这个问题。我们产生了bcl-x/半胱天冬酶-3双突变体，发现半胱天冬酶-3缺陷消除了有丝分裂后神经元凋亡的增加，但没有消除由bcl-x突变引起的造血细胞死亡和胚胎死亡的增加。与此相反，caspase-3，但不是bcl-x，缺陷改变了正常的神经元祖细胞凋亡的发生率，与缺乏Bcl-X-L的表达在胚胎皮质的增殖人口。因此，尽管Caspase-3在有丝分裂后神经元中位于Bcl-X-L的上游，但它独立地调节神经元创始细胞的凋亡。两者合计，这些结果建立了程序性细胞死亡在调节中枢神经系统中祖细胞群体的大小中的作用，该功能不同于细胞死亡在有丝分裂后神经元群体与突触后靶点匹配中的经典作用。
The number of neurons in the mammalian brain is determined by a balance between cell proliferation and programmed cell death. Recent studies indicated that Bcl-X-L prevents, whereas Caspase-3 mediates, cell death in the developing nervous system, but whether Bcl-X-L directly blocks the apoptotic function of Caspase-3 in vivo is not known. To examine this question. we generated bcl-x/caspase-3 double mutants and found that caspase-3 deficiency abrogated the increased apoptosis of postmitotic neurons but not the increased hematopoietic cell death and embryonic lethality caused by the bcl-x mutation. In contrast, caspase-3, but not bcl-x, deficiency changed the normal incidence of neuronal progenitor cell apoptosis, consistent with the lack of expression of Bcl-X-L in the proliferative population of the embryonic cortex. Thus, although Caspase-3 is epistatically downstream to Bcl-X-L in postmitotic neurons, it independently regulates apoptosis of neuronal founder cells. Taken together, these results establish a role of programmed cell death in regulating the size of progenitor population in the central nervous system, a function that is distinct from the classic role of cell death in matching postmitotic neuronal population with postsynaptic targets.