FUNCTION OF BCL-W IN MURINE DEVELOPMENT

BCL-W 在小鼠发育中的功能

• 批准号: 6387950
• 负责人: GRANT R MACGREGOR
• 金额: $ 14.33万
• 依托单位: EMORY UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 1998
• 资助国家: 美国
• 起止时间: 1998-05-15 至 2003-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6387950
• 关键词: BCL2 gene /protein; Sertoli cells; alleles; apoptosis; developmental genetics; electron microscopy; electroporation; extracellular matrix; flow cytometry; gene expression; gene targeting; genetic regulation; genetically modified animals; histopathology; immunocytochemistry; laboratory mouse; mammalian embryology; polymerase chain reaction; protein structure function; protooncogene; spermatogenesis; western blottings

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.

细胞凋亡调控中的缺陷与多种