CONDITIONAL MUTAGENESIS OF FIBROBLAST GROWTH FACTORS

描述（改编自申请人的描述）：先天性畸形 是婴儿和儿童发病和死亡的主要原因。 了解控制正常发育的遗传和分子程序 将提高我们理解、诊断并最终预防此类疾病的能力， 畸形指导肢体形成的发展计划在 胚胎的其他区域;肢体发育机制的发现 为了解其他器官和结构是如何形成的提供了有用的见解。 成纤维细胞生长因子（FGF）是在许多细胞中起作用的信号分子。 关键的发展路径。FGF在人类发展中的重要性 人类综合征，如Apert，Pfeiffer， 和Crouzon综合征是由FGF受体突变引起的。的目标 拟议的项目是确定FGF4和FGF8在早期 肢体发育小鼠生殖系中Fgf8或Fgf4的破坏 导致早期胚胎死亡，阻止检查他们的作用， 后来的发展过程。为了避免这种致命性， 产生了携带失活的Fgf4和Fgf8的条件突变， 以发育调节和组织限制的方式。这些小鼠 存活下来，显示出现有FGF模型无法预测的肢体表型 这些新问题是本建议的基础。 细胞间信号传导、细胞死亡和增殖的改变， 将表征导致Fgf8条件突变体中肢体缺陷的基因。 FGF8和FGF4可能的功能冗余将通过同时进行的免疫组化试验来测试。 破坏肢体中的这些基因。为了研究Fgf 8在肢体中的作用， 启动时，它将在小鼠胚胎的中间中胚层中被消融。 为实现这些目标而开发的试剂也将使有条件 突变系统是研究这些基因在 小鼠胚胎发育的其他区域，包括心血管 系统Capecchi博士的额外研究培训和 MCSDA将为Moon博士开始她的独立研究生涯做好准备 研究脊椎动物发育的基本调控途径。 最终，这些知识将帮助我们了解这些变化是如何发生的。 无论是遗传的还是环境的， 在婴儿和儿童身上。

DESCRIPTION (Adapted from applicant's description): Congenital malformations are a major cause of morbidity and mortality in infants and children. Knowledge of the genetic and molecular programs that govern normal development will improve our ability to understand, diagnose and eventually, prevent such malformations. Developmental programs that guide limb formation operate in other regions of the embryo; discoveries in mechanisms of limb development provide useful insight into how other organs and structures are formed. Fibroblast Growth Factors (FGFs) are signaling molecules that function in many critical developmental pathways. The importance of FGFs in human development was confirmed by discoveries that human syndromes, such as Apert, Pfeiffer, and Crouzon syndromes are caused by mutations in FGF receptors. The goal of the proposed project is to determine the roles of FGF4 and FGF8 during early limb development. Disruption of either Fgf8 or Fgf4 in the germline of mice results in early embryonic lethality, preventing examination of their roles in later developmental processes. To circumvent this lethality, mice were generated bearing conditional mutations of Fgf4 and Fgf8 that were inactivated in a developmentally-regulated and tissue-restricted manner. These mice survive, display limb phenotypes not predicted by existing models of FGF function and provoke new questions that are the basis of this proposal. Alterations in intercellular signaling, cell death and proliferation that result in limb defects in Fgf8 conditional mutants will be characterized. Possible functional redundancy of FGF8 and FGF4 will be tested by simultaneous disruption of these genes in the limb. To examine the role of Fgf8 in limb initiation, it will be ablated in the intermediate mesoderm of mouse embryos. Reagents developed to achieve these aims will also make the conditional mutagenesis system a powerful tool to investigate the role of these genes in other regions of the developing mouse embryo, including the cardiovascular system. Additional research training with Dr. Capecchi and the support of a MCSDA will prepare Dr. Moon to begin her independent research career investigating fundamental regulatory pathways in vertebrate development. Ultimately, this knowledge will help us to understand how alterations in those pathways, whether genetic or environmental, result in congenital malformations in infants and children.