FUNCTION OF BCL-W IN MURINE DEVELOPMENT

细胞凋亡调控的缺陷与多种细胞凋亡相关。 人类疾病包括艾滋病、癌症和神经退化。 BCL-2是 一个不断扩大的相关基因产物家族的创始成员， 在人类胚胎发育和成年过程中控制细胞凋亡 体内平衡 然而，涉及的基因数量，发育 它们所调节的过程以及它们在多大程度上重叠， 功能不太清楚。 我们发现了一名新成员 BCL-2基因家族命名为Bcl-w。 鼠标 缺乏Bcl-w的小鼠表现出可变的生长缺陷， 严重的睾丸萎缩 睾丸表型包括一个停滞， 生殖细胞发育，随后是生殖细胞和支持细胞的丧失。 分子生物学分析表明BCL-w与Bcl-2密切相关 并在相似的胚胎和成体组织中表达。 我们假设 Bcl-w介导胚胎发生和成年期间的细胞存活 通过调节离散组织中的细胞凋亡来维持体内平衡。 为了验证这一 假设，我们提出了四组实验。 首先我们将 BCL-w在小鼠胚胎发育过程中的表达模式 发育和成人组织中。 第二，我们将确定基本的 通过分析Bcl-w在发育过程中的作用程度， 缺乏Bcl-w的胚胎和成年小鼠中的程序性细胞死亡。 第三、 我们将通过测定Bcl-w在精子发生中的作用， (a)如果Bcl-w以细胞自主的方式对于单倍体胚是必需的 细胞发育和（B）是否与细胞外 基质影响支持细胞的生存在没有BCL-w。 第四，我们将确定Bcl-2是否补偿了细胞功能的丧失。 通过分析缺乏Bcl-w和Bcl-2的动物。 结果 将提供关于这个新成员的功能的新见解， Bcl-2基因家族在哺乳动物发育中作用 这样的信息可以 最终用于帮助开发人类疾病的分子疗法 由失调的细胞凋亡引起。

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.