RETINOIC ACID REGULATED GENES AND EMBRYOS

视黄酸调节基因和胚胎

• 批准号: 6044989
• 负责人: MELISSA B ROGERS
• 金额: $ 30.91万
• 依托单位: UNIVERSITY OF SOUTH FLORIDA
• 依托单位国家: 美国
• 财政年份: 1994
• 资助国家: 美国
• 起止时间: 1994-07-15 至 2004-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6044989
• 关键词: beta galactosidase; bone morphogenetic proteins; early embryonic stage; gene induction /repression; laboratory mouse; mammalian embryology; retinoate; teratogens

DESCRIPTION (adapted from investigator's abstract): Retinoids and their receptors directly modulate the transcription of specific genes, whose products influence growth, differentiation, or apoptosis. Alternatively, retinoid-activated transcription factors can stimulate cascades of signaling that indirectly alter a cell behavior. Thus, retinoids directly and indirectly initiate profound developmental changes. The investigators have shown that retinoic acid (RA) and bone morphogenetic proteins (BMPs) 2 and 4, interact to influence embryonic cell behavior. First, RA directly induces the Bmp2 gene. Second, cells exposed to RA or BMP2 or BMP4 alone or the combination of RA and a BMP behave differently. Changes in differentiation, growth rate, and the induction of apoptosis occur. The proposed experiments will augment our understanding of developmental and teratogenic mechanisms involving directly activated genes, including Bmp2. Aim 1. To determine whether or not the Bmp2 retinoic acid response element (RARE) is required for normal Bmp2 expression in mice. This aim will test the hypothesis that an endogenous retinoid signal is necessary for Bmp2 expression by comparing the developmental expression of B-galactosidase reporter genes driven by Bmp2 sequences containing the RARE to those lacking the RARE. Aim 2. To determine whether or not teratogenic levels of retinoids induce aberrant Bmp2 expression. This aim will test the hypothesis that aberrant Bmp2 expression is induced by retinoids by examining the expression of ,B-galactosidase reporter genes driven by Bmp2 sequences in RA-treated embryos. Aim 3. To elucidate the genetic regulatory elements controlling the expression of the Bmp2 gene in F9 embryonal carcinoma cells induced to differentiate into parietal endoderm by RA and increased cAMP levels. This aim will continue our systematic in vitro dissection of the genetic elements controlling Bmp2 expression by identifying the cAMP response element that modulates transcription only in RA-treated cells. Aim 4. To identify genes directly activated by RA by trapping murine RAREs in yeast. This aim will identify genes directly induced by RA and thus primary in controlling signaling cascades leading to changes in cell behavior.

描述（改编自研究者摘要）：类维生素A及其 受体直接调节特定基因的转录，其产物 影响生长、分化或凋亡。可选择地， 类维生素A激活的转录因子可以刺激信号级联 间接地改变细胞行为。因此，类维生素A直接和间接 引发了深刻的发展变化。调查人员表明， 视黄酸（RA）和骨形态发生蛋白（BMP）2和4相互作用， 影响胚胎细胞行为。首先，RA直接诱导Bmp 2基因。 第二，细胞暴露于单独的RA或BMP 2或BMP 4或RA和BMP 2或BMP 4的组合。 BMP的行为不同。分化、生长速度和细胞周期的变化 发生细胞凋亡诱导。拟议的实验将增强我们的 了解发育和致畸机制， 激活的基因，包括Bmp 2。目标1.为了确定Bmp 2是否 视黄酸反应元件（RARE）是正常Bmp 2表达所必需的。 小鼠这一目的将检验内源性类维生素A信号是 通过比较由含有RARE的Bmp 2序列驱动的B-半乳糖苷酶报告基因的发育表达， 对于那些缺乏稀有。 目标二。以确定是否致畸水平 类维生素A诱导Bmp 2表达异常。这一目标将检验这一假设 Bmp 2的异常表达是由维甲酸诱导的， 在RA处理的胚胎中，由Bmp 2序列驱动的B-半乳糖苷酶报告基因。 目标3.阐明控制表达的遗传调控元件 Bmp 2基因在F9胚胎癌细胞中诱导分化为 壁内胚层的RA和增加的cAMP水平。这一目标将继续我们的 控制Bmp 2的遗传元件的系统性体外解剖 通过鉴定调节cAMP表达的cAMP反应元件， 仅在RA处理的细胞中转录。目标4。直接识别基因 通过在酵母中捕获鼠RARE而被RA激活。这一目标将确定基因 直接由RA诱导，因此主要控制信号级联反应 导致细胞行为的改变。