Departamento de Anatomía y Biología Celular, Universidad de Cantabria/IFIMAV, Santander, Spain.
Apoptosis. 2010 Mar;15(3):365-75. doi: 10.1007/s10495-009-0444-5.
Physiological cell death is a key mechanism that ensures appropriate development and maintenance of tissues and organs in multicellular organisms. Most structures in the vertebrate embryo exhibit defined areas of cell death at precise stages of development. In this regard the areas of interdigital cell death during limb development provide a paradigmatic model of massive cell death with an evident morphogenetic role in digit morphogenesis. Physiological cell death has been proposed to occur by apoptosis, cellular phenomena genetically controlled to orchestrate cell suicide following two main pathways, cytochrome C liberation from the mitochondria or activation of death receptors. Such pathways converge in the activation of cysteine proteases known as caspases, which execute the cell death program, leading to typical morphologic changes within the cell, termed apoptosis. According to these findings it would be expected that caspases loss of function experiments could cause inhibition of interdigital cell death promoting syndactyly phenotypes. A syndactyly phenotype is characterized by absence of digit freeing during development that, when caused by absence of interdigital cell death, is accompanied by the persistence of an interdigital membrane. However this situation has not been reported in any of the KO mice or chicken loss of function experiments ever performed. Moreover histological analysis of dying cells within the interdigit reveals the synchronic occurrence of different types of cell death. All these findings are indicative of caspase alternative and/or complementary mechanisms responsible for physiological interdigital cell death. Characterization of alternative cell death pathways is required to explain vertebrate morphogenesis. Today there is great interest in cell death via autophagy, which could substitute or act synergistically to the apoptotic pathway. Here we discuss what is known about physiological cell death in the developing interdigital tissue of vertebrate embryos, paying special attention to the avian species.
生理性细胞死亡是确保多细胞生物组织和器官适当发育和维持的关键机制。脊椎动物胚胎中的大多数结构在发育的特定阶段都表现出明确的细胞死亡区域。在这方面，肢发育过程中的指间细胞死亡区域为大量细胞死亡提供了一个典范模型，其在指骨形态发生中具有明显的形态发生作用。已经提出生理性细胞死亡通过细胞凋亡发生，这是一种遗传控制的细胞自杀现象，通过两种主要途径来协调细胞自杀，即线粒体中细胞色素 C 的释放或死亡受体的激活。这些途径在称为半胱氨酸蛋白酶（caspases）的胱天蛋白酶的激活中汇聚，这些蛋白酶执行细胞死亡程序，导致细胞内出现典型的形态变化，称为凋亡。根据这些发现，预计 caspase 功能丧失实验可能会导致指间细胞死亡抑制，从而促进并指表型。并指表型的特征是在发育过程中没有手指游离，当由指间细胞死亡缺失引起时，伴随着指间膜的持续存在。然而，在任何 KO 小鼠或鸡功能丧失实验中都没有报道过这种情况。此外，对指间死亡细胞的组织学分析揭示了不同类型细胞死亡的同步发生。所有这些发现都表明 caspase 具有替代和/或互补机制，负责生理性指间细胞死亡。为了解释脊椎动物形态发生，需要对替代细胞死亡途径进行特征描述。今天，人们对自噬介导的细胞死亡非常感兴趣，自噬可能替代或与凋亡途径协同作用。在这里，我们讨论了在脊椎动物胚胎发育的指间组织中已知的生理性细胞死亡，特别关注禽类。
