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（改编自研究者的摘要）：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。或者， 类维生素A激活的转录因子可以刺激信号级联反应 间接改变细胞行为。因此，类维生素A直接和间接 引发深刻的发展变革。研究人员表明 视黄酸 (RA) 和骨形态发生蛋白 (BMP) 2 和 4 相互作用 影响胚胎细胞的行为。首先，RA直接诱导Bmp2基因。 其次，细胞暴露于单独的 RA 或 BMP2 或 BMP4 或 RA 和 BMP4 的组合 BMP 的行为有所不同。分化、增长率和产量的变化 诱导细胞凋亡发生。拟议的实验将增强我们的 了解直接涉及的发育和致畸机制 激活基因，包括 Bmp2。目的 1. 判断 Bmp2 是否 视黄酸反应元件 (RARE) 是正常 Bmp2 表达所必需的 老鼠。该目标将检验内源性视黄醇信号是 通过比较由包含 RARE 的 Bmp2 序列驱动的 B-半乳糖苷酶报告基因的发育表达，对于 Bmp2 表达是必需的 对于那些缺乏稀有的人。 目标 2. 确定是否致畸水平 类视黄醇诱导异常的 Bmp2 表达。该目标将检验假设 通过检查 Bmp2 的表达，发现异常的 Bmp2 表达是由类视黄醇诱导的 ,B-半乳糖苷酶报告基因由 RA 处理的胚胎中的 Bmp2 序列驱动。 目标 3. 阐明控制表达的遗传调控元件 F9胚胎癌细胞中Bmp2基因的诱导分化 RA 导致壁层内胚层 cAMP 水平升高。这一目标将继续我们 控制 Bmp2 的遗传元件的系统体外解剖 通过识别调节 cAMP 反应元件来表达 仅在 RA 处理的细胞中转录。目标 4. 直接识别基因 RA 通过将小鼠 RARE 捕获在酵母中来激活。这个目标将识别基因 由 RA 直接诱导，因此主要控制信号级联 导致细胞行为的改变。