FUNCTION OF BCL-W IN MURINE DEVELOPMENT

细胞凋亡调控方面的缺陷与多种 人类疾病包括艾滋病、癌症和神经退行性变。BCL-2是 一个不断扩大的相关基因产品家族的创始成员 人类胚胎发育和成年过程中的细胞凋亡控制 动态平衡。然而，涉及的基因数量，发育 它们监管的过程以及它们重叠的程度 功能还没有被很好地理解。我们已经确定了一名新的成员 BCL-2基因家族随机插入突变命名为Bc l-w 那只老鼠。缺乏Bc l-w的小鼠表现出不同的生长缺陷和 严重的睾丸萎缩。睾丸表型包括一种停滞在 生殖细胞发育伴随着生殖细胞和支持细胞的丧失。 分子分析表明，bclw与bcl2密切相关 在类似的胚胎和成人组织中也有表达。我们假设 Bclw在胚胎发育和成体细胞存活中的作用 通过调节离散组织中的细胞凋亡来实现动态平衡。为了测试这一点 假设，我们提出了四组实验。首先，我们会 Bclw在小鼠胚胎发育过程中的表达特征 在发育和成体组织中。第二，我们将确定必要的 通过分析Bclw在发育过程中的作用程度 胚胎和缺乏Bclw的成年小鼠的程序性细胞死亡。第三, 我们将通过检测Bclw在精子发生中的作用来研究它的功能。 (A)单倍体生殖细胞是否需要以细胞自主方式表达bc l-w 细胞发育和(B)是否与细胞外相互作用 在缺乏bclw的情况下，基质影响支持细胞的存活。 第四，我们将确定Bcl2是否补偿了细胞功能的丧失 通过分析同时缺乏Bc l-w和Bc l-2的动物来检测BCL-w。结果是 将提供关于这一新成员的功能的新见解 哺乳动物发育中的Bcl-2基因家族。此类信息可以 最终被用来帮助开发人类疾病的分子疗法 这是由不受管制的细胞凋亡引起的。

Defects in the regulation of apoptosis are associated with a variety of human disease including AIDS, cancer and neurodegeneration. BCL-2 is the founder member of an expanding family of related gene products that control apoptosis during human embryonic development and adult homeostasis. However, the number of genes involved, the developmental processes that they regulate and the extent to which they overlap in function are not well understood. We have identified a new member of the BCL-2 gene family named Bcl-w by random insertional mutagenesis in the mouse. Mice lacking Bcl-w display a variable growth deficit and a severe testicular atrophy. The testis phenotype involves an arrest in germ cell development followed by a loss of both germ and Sertoli cells. A molecular analysis indicates that BCL-w is closely related to Bcl-2 and is expressed in similar embryonic and adult tissues. We hypothesize that Bcl-w mediates cell survival during embryogenesis and adult homeostasis by regulating apoptosis in discrete tissues. To test this hypothesis, we propose four groups of experiments. First we will characterize the expression pattern of BCL-w during mouse embryonic development and in adult tissues. Second, we will identify essential functions for Bcl-w during development by analyzing the extent of programmed cell death in embryos and adult mice lacking Bcl-w. Third, we will study the function of Bcl-w in spermatogenesis by determining (a) if Bcl-w is required in a cell autonomous manner for haploid germ cell development and (b) whether interaction with the extracellular matrix influences Sertoli cell survival in the absence of BCL-w. Fourth, we will determine if Bcl-2 compensates for loss of function of BCL-w by analyzing animals that lack both Bcl-w and Bcl-2. The results will provide novel insight regarding the function of this new member of the Bcl-2 gene family in mammalian development. Such information may ultimately be used to help develop molecular therapies of human disease that arise from deregulated apoptosis.