THE ROLE OF FGF RECPETORS IN LENS DEVELOPMENT

对于大多数细胞类型，诱导细胞在体内分化的分子机制尚不清楚，但这些过程对人类健康的几乎每个方面都是至关重要的。 透镜已经成为一个越来越受欢迎的器官系统，在分子水平上剖析这些发育过程。 这部分是由于它的简单性和可访问性。 透镜是脊椎动物一生中为数不多的正常持续生长的器官之一。 这种生长是连续的、特征性的增殖和分化模式的结果。 透镜上皮细胞是透镜的增殖组分，并且这些上皮细胞被诱导分化成纤维细胞，这是由一种尚未确定的分子信号引起的。 成纤维细胞生长因子（FGF）具有诱导透镜上皮细胞和转基因小鼠透镜纤维细胞分化的能力。 虽然在整个发育过程中有几种FGF在眼睛中表达，但尚不清楚这些FGF是否在透镜纤维细胞分化中起重要作用。 FGF被认为通过FGF受体酪氨酸激酶（FGFR）发挥其大部分生物学效应。 在发育中的透镜中有三种FGFR基因表达，并且所有这三种基因都存在无效突变。 FGFR 1和FGFR 2中的纯合无效突变导致透镜形成之前的胚胎死亡，并且FGFR 3缺陷的小鼠具有明显正常的晶状体。 本项目的目标是确定FGFRs是否在透镜纤维细胞分化过程中发挥重要作用。 为此，将使用P1噬菌体的Cre/loxP系统开发在透镜上皮中缺失特异性基因表达的方法。这些小鼠将与携带FGFR 1或FGFR 2条件突变的小鼠杂交。 这些策略应避免传统构建的无效等位基因所遇到的胚胎生存力问题。 除了确定任何单个FGFR是否对纤维细胞分化是必需的之外，我们还将产生多种FGFR缺陷的小鼠，以确定单个FGFR的损失是否可以通过其他FGFR的表达来补偿。

The molecular mechanisms by which cells are induced to differentiate in vivo is not understood for most cell types, yet these processes are fundamental to virtually every aspect of human health. The lens has become an increasingly popular organ system to dissect these developmental processes at the molecular level. This is due, in part, to its simplicity and accessibility. The lens is one of the few organs that normally continue to grow throughout the vertebrate life-span. This growth is a consequence of a continuous, characteristic pattern of proliferation and differentiation. Lens epithelial cells are the proliferative component of the lens, and these epithelial cells are induced to differentiate into fiber cells by an, as yet, undetermined molecular signal. Fibroblast growth factors (FGFs) possess the ability to induce lens fiber cell differentiation both in lens epithelial explants and in transgenic mice. While there are several FGFs expressed in the eye throughout development, it is unknown if these play an essential role in lens fiber cell differentiation. FGFs are thought to exert most of their biological effects through FGF receptor tyrosine kinases (FGFRs). There are three FGFR genes expressed in the developing lens, and null mutations exist for all three of these. Homozygous null mutations in FGFR1 and FGFR2 lead to embryonic lethality prior to lens formation, and mice deficient in FGFR3 have apparently normal lenses. The goal of this project is to determine if FGFRs play an essential role in the process of lens fiber cell differentiation. To do this, a method to delete specific gene expression in the lens epithelium will be developed using the Cre/loxP system of P1 bacteriophage. These mice will be crossed to mice carrying conditional mutations in FGFR1 or FGFR2. These strategies should avoid the problems of embryonic viability encountered with the traditionally constructed null alleles. In addition to determining if any single FGFR is essential for fiber cell differentiation, we will also create mice deficient in multiple FGFRs to determine if the loss of a single FGFR can be compensated for by the expression of other FGFRs.