FUNCTION OF BCL-W IN MURINE DEVELOPMENT

BCL-W 在小鼠发育中的功能

• 批准号: 6765086
• 负责人: GRANT R MACGREGOR
• 金额: $ 9.18万
• 依托单位: UNIVERSITY OF CALIFORNIA-IRVINE
• 依托单位国家: 美国
• 财政年份: 2003
• 资助国家: 美国
• 起止时间: 2003-07-01 至 2004-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6765086
• 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.

细胞凋亡调节的缺陷与多种因素有关。 人类疾病包括艾滋病、癌症和神经退行性疾病。 BCL-2 是 不断扩大的相关基因产品家族的创始人成员 控制人类胚胎发育和成人过程中的细胞凋亡 体内平衡。 然而，涉及的基因数量、发育 它们监管的流程以及它们重叠的程度 功能不太了解。 我们已经确定了一位新成员 通过随机插入诱变将 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和 严重的睾丸萎缩。 睾丸表型涉及停滞 生殖细胞发育，随后生殖细胞和支持细胞均丧失。 分子分析表明 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 在胚胎发生和成体过程中介导细胞存活 通过调节离散组织中的细胞凋亡来实现稳态。 为了测试这个 假设，我们提出四组实验。 首先我们将 表征小鼠胚胎期间 BCL-w 的表达模式 发育和成人组织中。 其次，我们将确定必要的 通过分析 Bcl-w 在开发过程中的功能 缺乏 Bcl-w 的胚胎和成年小鼠中的程序性细胞死亡。 第三， 我们将通过确定来研究 Bcl-w 在精子发生中的功能 (a) 如果单倍体胚芽以细胞自主方式需要 Bcl-w 细胞发育和（b）是否与细胞外相互作用 在缺乏 BCL-w 的情况下，基质会影响支持细胞的存活。 第四，我们将确定 Bcl-2 是否可以补偿 Bcl-2 的功能丧失。 BCL-w 通过分析同时缺乏 Bcl-w 和 Bcl-2 的动物。 结果 将为这个新成员的功能提供新颖的见解 哺乳动物发育中的 Bcl-2 基因家族。 此类信息可能 最终用于帮助开发人类疾病的分子疗法 由细胞凋亡失调引起。

项目成果

Heteroplasmy of mouse mtDNA is genetically unstable and results in altered behavior and cognition.

• DOI: 10.1016/j.cell.2012.09.004
• 发表时间: 2012-10-12
• 期刊: Cell
• 影响因子: 64.5
• 作者: Sharpley MS;Marciniak C;Eckel-Mahan K;McManus M;Crimi M;Waymire K;Lin CS;Masubuchi S;Friend N;Koike M;Chalkia D;MacGregor G;Sassone-Corsi P;Wallace DC
• 通讯作者: Wallace DC

An extreme bias in the germ line of XY C57BL/6<->XY FVB/N chimaeric mice.

XY C57BL/6<->XY FVB/N 嵌合小鼠种系存在极端偏差。

• DOI: 10.1530/rep.0.1240377
• 发表时间: 2002
• 期刊: Reproduction (Cambridge, England)
• 作者: MacGregor,GR

Developmental regulation of Bcl-2 family protein expression in the involuting mammary gland.

退化乳腺中 Bcl-2 家族蛋白表达的发育调控。

• DOI: 10.1242/jcs.112.11.1771
• 发表时间: 1999
• 期刊: Journal of cell science
• 影响因子: 4
• 作者: Metcalfe,AD;Gilmore,A;Klinowska,T;Oliver,J;Valentijn,AJ;Brown,R;Ross,A;MacGregor,G;Hickman,JA;Streuli,CH
• 通讯作者: Streuli,CH