FUNCTIONAL ANALYSIS OF ACTIVINS DURING DEVELOPMENT

在哺乳动物中，大约有10万个基因控制着 生物体的发育。为了使开发正常进行，有 一定是成千上万个这样的基因协同作用 存在的任何给定细胞中的产品。从受精开始， 这些基因产物在胚胎期间的精确表达是必需的， 胎儿、出生后和成人的发育。偶一的异常合成 这些基因产物中的一种可能是灾难性的-出生缺陷，癌症， 当这种发育时，不孕不育，甚至死亡都是可能的 程序被更改。为了充分了解人类的这些过程，它 是有必要的生理模型，以密切模拟 在人类创造过程中发生的发育事件。 为此，我们选择小鼠作为我们的 学习。现在有可能修改小鼠基因组以产生 具有精确基因突变的小鼠品系。使用这项技术， 我们实验室已经创造了几个有出生缺陷的模型。为 例如，激活素BetaA和卵泡抑素基因突变的小鼠 出生时死亡并患有腭裂，这是人类常见的先天缺陷 病因不明。此外，小鼠激活素受体基因突变 II型基因有骨骼和面部的异常，类似于 人类皮埃尔-罗宾综合征；患有这种综合征的人类新生儿 下颌骨缺陷，导致呼吸窘迫，必须 立即手术矫正。在这项拨款建议中，我们将 利用这些先前创建的鼠标模型以及其他 对此进行研究的模型(即缺乏激活素Betac和BetaE的小鼠 复杂的信号转导系统。具体目标是：1)界定 肝脏特异性转化生长因子-β超家族成员激活素的功能 Betac和BetaE；2)执行激活素BETAB“敲门”以尝试 抢救激活素βA基因敲除小鼠；3)研究出生后 卵泡抑素和激活素βA在诱导基因敲除中的作用 系统。利用这些小鼠作为活体哺乳动物模型的未来研究 系统将使我们能够更充分地了解相互关联的角色 这些蛋白质在哺乳动物发育和生理学中的作用。

In mammals, there are approximately 100,000 genes which govern the development of an organism. For development to proceed normally, there must be coordinate interaction of tens of thousands of these gene products in any given cell of the being. Beginning with fertilization, precise expression of these gene products is required during embryonic, fetal, postnatal, and adult development. Aberrant synthesis of even one of these gene products can be disastrous - birth defects, cancer, infertility, and even death are all possible when this developmental program is altered. To fully understand these processes in humans, it is necessary to have physiological models that closely mimic developmental events which occur during the creation of a human being. Toward this end, we have chosen the mouse as the mammalian model for our studies. It is now possible to modify the mouse genome to generate strains of mice with precise genetic mutations. Using this technology, our laboratory has created several models which have birth defects. For example, mice with mutations in the activin betaA and follistatin genes die at birth and have cleft palate, a common birth defect in humans of unknown etiology. In addition, mice a mutations in the activin receptor type II gene have skeletal and facial abnormalities which mimic the human Pierre-Robin syndrome; human newborns with this syndrome have defects in the mandible, leading to respiratory distress which must be surgically corrected immediately. In this grant proposal, we will utilize these previously created mouse models as well as additional models (i.e., mice lacking activins betaC an betaE) to study this complex signal transduction system. The Specific Aims are: 1) Define the functions of the liver-specific TGF-beta-superfamily members, activins betaC and betaE; 2) Perform an activin betaB "knockin" to attempt a rescue of activin betaA knockout mice; and 3) Study the postnatal functions of follistatin and activin betaA using inducible knockout systems. Future studies using these mice as in vivo mammalian model systems will enable us to more fully understand the interrelated roles of these proteins in mammalian development and physiology.