Molecular mechanisms regulating optic fissure closure

调节视裂隙闭合的分子机制

• 批准号: 163250558
• 负责人: Professorin Dr. Kerstin Krieglstein
• 金额: --
• 依托单位: Forschungsgruppe Entwicklungsbiologie
• 依托单位国家: 德国
• 项目类别: Research Grants
• 财政年份: 2010
• 资助国家: 德国
• 起止时间: 2009-12-31 至 2013-12-31
• 项目状态: 已结题
• 来源: https://gepris.dfg.de/gepris/projekt/163250558?language=en
• 关键词: Molecular; mechanisms; regulating; optic; fissure

Eye development is an intricate process, ranging from the definition of the eye field, to optic vesicle evagination and differentiation of the neuroretina. After lens induction the dorsal retinal anlage extends and folds ventrally with its anterior and posterior parts. In the area where these latter parts will meet, an optic fissure is visible. During normal development, this optic fissure is only transiently present. The fissure closes by fusion of the anterior and posterior edges of the retinal parts. Defects of optic fissure closure, referred to as coloboma, can affect several eye structures like iris, choroidea or retina and may be combined with malformations of other parts of the central nervous system (CNS), and also other organs (i.e. heart and kidney). Gene mutations identified in affected patients as well as in mice have led to the proposal of a coloboma gene regulatory network. Although many genes, primarily transcription factors that lead to coloboma formation if altered have been identified, the link to effector molecules mediating the process is still elusive. From our preliminary work we know that loss of TGF-beta2 leads, in addition to numerous already described defects in eye development, to a lack of optic fissure closure and a hypercellular, disorganized retina. TGF-betas are a family of extracellular mediators regulating cell proliferation, differentiation, survival and death. The specific aim of the proposed project is to unravel the molecular and mechanistic details of how extracellular molecules such as TGF-beta orchestrate optic fissure closure and how TGF-beta dependent signaling integrates into the known coloboma gene network. The project is a joint effort of two laboratories with unique expertise in retina development in fish and mouse. The project will start by a systematic analysis of potential TGF-beta target genes using TGF-beta2 null mice in comparison to wild type litter mates at E13.5 (before optic fissure closure) and E16.5 (proliferation and differentiation of neuroretina), followed by appropriate bioinformatics processing and database analyses. Functional analysis of candidate genes will be done in fish. Furthermore, a retina-specific mouse line lacking TGF-beta signaling (Cre-Rx3 x TbR-IIflox/flox) will be generated to study TGF-beta induced retina development independent of mesenchyme-derived TGF-beta signaling.

眼睛发育是一个复杂的过程，从视野的定义到视神经囊泡的膨出和神经视网膜的分化。晶状体诱导后，视网膜背侧组织与其前部和后部一起向腹侧延伸和折叠。在这两部分相交的地方，可以看到视神经裂。在正常发育过程中，视神经裂只是暂时存在。裂口通过视网膜前部和后部边缘的融合而闭合。视神经裂隙闭合缺陷被称为先天性缺损，可影响虹膜、脉络膜或视网膜等几种眼部结构，并可能合并中枢神经系统（CNS）其他部位以及其他器官（即心脏和肾脏）的畸形。在受影响的患者和小鼠中发现的基因突变导致了结肠瘤基因调控网络的提出。虽然已经确定了许多基因，主要是导致结肠瘤形成的转录因子，但介导这一过程的效应分子的联系仍然难以捉摸。从我们的初步工作中，我们知道tgf - β 2的缺失，除了许多已经描述的眼睛发育缺陷外，还会导致视神经裂隙闭合不足和视网膜细胞过多、组织紊乱。tgf - β是一类调节细胞增殖、分化、存活和死亡的细胞外介质。该项目的具体目标是揭示细胞外分子如tgf - β如何协调视裂隙关闭的分子和机制细节，以及tgf - β依赖的信号如何整合到已知的结肠瘤基因网络中。该项目是两个在鱼类和小鼠视网膜发育方面具有独特专业知识的实验室的共同努力。该项目将首先使用tgf - β 2缺失小鼠与野生型胎仔在E13.5（视裂关闭前）和E16.5（神经视网膜的增殖和分化）时进行潜在tgf - β靶基因的系统分析，随后进行适当的生物信息学处理和数据库分析。候选基因的功能分析将在鱼类中进行。此外，将产生缺乏tgf - β信号的视网膜特异性小鼠系（Cre-Rx3 x TbR-IIflox/flox），以研究tgf - β诱导的独立于间质来源的tgf - β信号的视网膜发育。