Apaf1-dependent programmed cell death is required for inner ear morphogenesis and growth
Apaf1-dependent programmed cell death is required for inner ear morphogenesis and growth
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DOI：
10.1242/dev.01082
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发表时间：
2004-05-01
期刊：
影响因子：
4.6
通讯作者：
Salminen, M
中科院分区：
文献类型：
--
作者：
Cecconi, F;Roth, KA;Salminen, M
在内耳发育过程中，程序性细胞死亡发生在耳上皮的特定区域，但其意义和所涉及的分子仍不清楚。我们对小鼠突变体进行了分析，其中编码凋亡相关分子的基因已失活。 Apaf1基因的破坏导致内耳上皮细胞凋亡急剧减少、严重的形态发生缺陷以及膜迷路尺寸的显着减小，这表明Apaf1依赖性细胞凋亡途径对于正常的内耳发育是必需的。该途径很可能通过凋亡体复合物发挥作用，因为 caspase 9 突变小鼠也存在类似的缺陷。 Bcl2 样 (Bcl2l) 基因的失活导致发生凋亡的细胞数量总体增加，但不会引起任何主要的形态发生缺陷。相反，在发育缺陷的特定位置观察到细胞凋亡减少，表明 Bcl2l 产生的促凋亡亚型可能在内耳发育中发挥作用。在Apaf1(-/-)/Bcl2l(-/-)双突变体胚胎中，耳上皮中未检测到细胞死亡，表明耳上皮中抗凋亡Bcl2l亚型Bcl-X-L调节的细胞死亡是Apaf1依赖性的。此外，在所有分析的双突变体胚胎中，耳囊未能完全闭合。这些结果表明 Apaf1 和 Bcl2l 在内耳发育中发挥重要作用。
During inner ear development programmed cell death occurs in specific areas of the otic epithelium but the significance of it and the molecules involved have remained unclear. We undertook an analysis of mouse mutants in which genes encoding apoptosis-associated molecules have been inactivated. Disruption of the Apaf1 gene led to a dramatic decrease in apoptosis in the inner ear epithelium, severe morphogenetic defects and a significant size reduction of the membranous labyrinth, demonstrating that an Apaf1-dependent apoptotic pathway is necessary for normal inner ear development. This pathway most probably operates through the apoptosome complex because caspase 9 mutant mice suffered similar defects. Inactivation of the Bcl2-like (Bcl2l) gene led to an overall increase in the number of cells undergoing apoptosis but did not cause any major morphogenetic defects. In contrast, decreased apoptosis was observed in specific locations that suffered from developmental deficits, indicating that proapoptotic isoform(s) produced from Bcl2l might have roles in inner ear development. In Apaf1(-/-)/Bcl2l(-/-) double mutant embryos, no cell death could be detected in the otic epithelium, demonstrating that the cell death regulated by the anti-apoptotic Bcl2l isoform, Bcl-X-L, in the otic epithelium is Apaf1-dependent. Furthermore, the otic vesicle failed to close completely in all double mutant embryos analyzed. These results indicate important roles for both Apaf1 and Bcl2l in inner ear development.