Programmed Cell Death in Anterior Eye Development and Peters' Anomaly

描述（由申请人提供）：本项目的长期目标是描述视黄酸（RA）在眼透镜和眼前节发育早期调节程序性细胞死亡（PCD）的信号机制。在透镜形态发生中，这种精确控制的PCD对于透镜囊泡与上覆表面外胚层（或预期的角膜上皮）的正常分离是必不可少的。这种PCD的破坏，无论是通过基因突变还是通过人类胚胎发育过程中的环境损伤，都会导致一种致盲的先天性眼病，称为彼得斯异常，这是眼前段发育不全（ASD）的一种亚型。我们推测RA（维生素A代谢产物）和线粒体凋亡途径的激活在早期透镜发育过程中诱导PCD中起重要作用。提出了三个重叠的具体目标：1）我们的初步研究表明，在视黄醇脱氢酶10（Rdh 10），在RA合成的第一步酶的功能丧失突变，抑制PCD，并导致形成持久的透镜柄之间的透镜和角膜。这一发现表明，RA信号是必不可少的诱导PCD的晶状体-角膜分离在眼睛发育过程中。目的1：探讨在透镜囊泡发育过程中，RA诱导的凋亡信号与成纤维细胞生长因子（FGF）和骨形态发生蛋白（BMP）信号激活的细胞存活信号之间的相互作用。2)在目标2中，我们将描绘RA信号在先前建立的Pax 6-Foxe 3遗传通路中的位置。已知这两种转录因子在小鼠眼睛发育过程中对晶状体-角膜分离至关重要，这些基因的突变与人类的彼得斯异常有关。3)初步研究表明，在糖尿病缺陷型突变小鼠（例如，细胞色素cKA/KA敲入小鼠），形成持久的透镜柄并破坏正常的眼前节形态发生。为了更好地理解Peters异常儿童中严重先天性青光眼的致病机制，在目标3中，我们将通过使用线粒体死亡途径缺陷的突变小鼠模型来检查眼前段组织中发育异常的表现。综上所述，本项目将有助于RA信号在早期透镜发育过程中调控PCD的基础知识，并将对扩大我们对儿童Peters异常发病机制的理解产生重要影响。总的来说，这个项目研究了一个关键的，但被忽视的，眼睛发育的领域，并对儿科眼科学有重要的影响。

DESCRIPTION (provided by applicant): The long-term goal of this project is to delineate the signaling mechanisms of retinoic acid (RA) in the regulation of programmed cell death (PCD) during the early stage of ocular lens and anterior segment development. This precisely controlled PCD is essential for normal separation of the lens vesicle from the overlying surface ectoderm (or the prospective corneal epithelium) in lens morphogenesis. Disruption of this PCD, either by genetic mutations or by environmental insults during human embryogenesis, causes a blinding congenital eye disease, called Peters' anomaly, which is a subtype of anterior segment dysgenesis (ASD). We hypothesize that RA (a vitamin A metabolite) and activation of the mitochondrial apoptosis pathway play an essential role in the induction of PCD during early-stage lens development. Three overlapping specific aims are proposed: 1) Our preliminary studies indicate that loss-of-function mutation in retinol dehydrogenase 10 (Rdh10), an enzyme in the first step of RA synthesis, inhibits PCD and causes formation of a persistent lens stalk between the lens and cornea. This finding suggests that RA-signaling is essential for induction of PCD in lens-corneal separation during eye development. In Aim 1, we will explore the interactions between the RA- induced apoptotic signal and the cell survival signals activated by fibroblast growth factor (FGF) and bone morphogenic protein (BMP) signaling during lens vesicle development. 2) In Aim 2, we will delineate the position of RA-signaling in the previously established genetic pathway of Pax6-Foxe3. Both transcriptional factors are known to be essential for lens-corneal separation during mouse eye development, and mutations in these genes are linked to Peters' anomaly in humans. 3) Preliminary studies show that in the eyes of apoptosis-defective mutant mice (e.g., Cytochrome cKA/KA knockin mice), a persistent lens stalk is formed and disrupts normal anterior segment morphogenesis. To better understand the pathogenic mechanisms of severe congenital glaucoma in children with Peters' anomaly, in Aim 3, we will examine the manifestations of developmental abnormalities in the anterior segment tissues by using the mutant mice models that are defective in the mitochondrial death pathway. In summary, this project will contribute to the fundamental knowledge of RA-signaling in regulation of PCD during early lens development, and will have an important impact on expanding our understanding of the pathogenesis of Peters' anomaly in children. Overall, this project examines a critical, though neglected, area of eye development and has important implications for pediatric ophthalmology.