Regulation of Eye Morphogenesis

眼睛形态发生的调节

• 批准号: 10660203
• 负责人: SABINE FUHRMANN
• 金额: $ 45.41万
• 依托单位: VANDERBILT UNIVERSITY MEDICAL CENTER
• 依托单位国家: 美国
• 财政年份: 2015
• 资助国家: 美国
• 起止时间: 2015-09-01 至 2027-03-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10660203
• 关键词: Actins; Anophthalmos; Binding; Blindness; Candidate Disease Gene; Cell Line; Childhood; Coloboma; Complex; Congenital Abnormality; Cytoskeleton; Data; Defect; Development; Embryo; Embryonic Development; Enhancers; Ensure; Equilibrium; Essential Genes; Event; Exhibits; Eye; Eye Development; Eye diseases; Filopodia; Funding; Genes; Goals; Growth; Homeostasis; Human; Image; In Vitro; Individual; Knowledge; Maintenance; Mesenchyme; Microphthalmos; Molecular; Molecular Motors; Morphogenesis; Motor; Mutant Strains Mice; Mutation; Myosin ATPase; Neurofibromin 2; Nuclear Translocation; Optic vesicle; Optics; Organ Size; Pathway interactions; Process; Production; Proliferating; Regulation; Regulatory Pathway; Research; Resolution; Role; Severities; Signal Pathway; Signal Transduction; Structure of retinal pigment epithelium; Tertiary Protein Structure; Therapeutic; Tissues; Transcriptional Regulation; Tumor Suppressor Genes; directed differentiation; experimental study; gene regulatory network; malformation; neuroepithelium; novel; optic cup; regenerative; rho GTP-Binding Proteins; stem cell division; tissue regeneration; tumor

Project Summary Congenital ocular malformations such as microphthalmia, anophthalmia and coloboma are prevalent in 1 in 3- 4,000 individuals and are the cause for over 25% of childhood blindness worldwide. Defective closure of the optic fissure (coloboma) alone may account up to 10% of childhood blindness. Therefore, it is vitally important to understand the molecular mechanisms underlying ocular development. While several causative genes are identified, more effort is required to define the downstream targets and events underlying eye morphogenesis. In our previous project, we showed that Porcn signaling needs to be tightly regulated during optic cup formation and optic fissure closure. The Rho GTPase Cdc42 is critical for optic vesicle invagination and growth of the optic cup, as well for optic fissure closure. Higher resolution Airyscan imaging revealed the presence of actin-rich, filopodia-like extensions in the closing fissure. Important gaps in our understanding are how the fissure margins make contact during the closure process and how growth of optic cup domains is coordinated. The molecular, unconventional motor Myosin X (Myo10) can induce filopodia formation and is a novel candidate gene for microphthalmia in humans. Our preliminary data shows that Myo10 mutant mice can exhibit coloboma and microphthalmia. In Aim 1 of this renewal application, we propose to investigate the role of Myo10 in ocular tissues using inducible conditional inactivation. Furthermore, the Hippo signaling pathway is a novel key regulatory pathway controlling distinct processes during mammalian eye development. We discovered an early role of the upstream regulator neurofibromin 2 (Nf2) in restricting retinal pigment epithelium (RPE) proliferation in the invaginating optic cup, critical for proper optic fissure closure. In Aim 2, we propose to examine how Nf2 disruption causes extended RPE proliferation in the early optic cup. In addition, our preliminary data shows an early effect on ocular growth by modulation of Hippo signaling in ocular and periocular tissues. In Aim 3, we will analyze the precise role of Yap/Taz and Nf2 during early optic cup morphogenesis. The studies proposed here will be a critical step toward an understanding of the cellular and molecular mechanisms controlling eye morphogenesis and important for advancing treatment and regenerative efforts of ocular diseases.

项目摘要 先天性眼部畸形，如小眼球，无眼球和缺损是普遍存在的，在1991年的3- 4,000人，是全球25%以上儿童失明的原因。关闭缺陷 光是视神经裂（缺损）就可占儿童失明的10%。因此， 以了解眼部发育的分子机制。虽然一些致病基因是 确定，需要更多的努力，以确定下游目标和事件的眼睛形态发生。 在我们之前的项目中，我们发现在视杯形成过程中， 形成和视裂闭合。Rho GTdR Cdc 42对视泡内陷和生长至关重要 以及视神经裂闭合。更高分辨率的Airyscan成像显示存在 肌动蛋白丰富，丝状伪足样的延伸在关闭的裂缝。我们理解的重要差距是， 裂隙边缘在闭合过程中接触以及视杯域的生长如何协调。 分子，非传统的马达肌球蛋白X（Myo 10）可以诱导丝状伪足的形成，是一种新的 人类小眼症的候选基因我们的初步数据显示，Myo 10突变小鼠可以表现出 缺损和小眼球。在本更新申请的目标1中，我们建议研究以下因素的作用： 使用可诱导条件失活的眼组织中的Myo 10。此外，Hippo信号通路是一种 哺乳动物眼睛发育过程中控制不同过程的新的关键调控途径。我们 发现了上游调节因子神经纤维蛋白2（Nf 2）在限制视网膜色素中的早期作用， 内陷视杯中的视网膜上皮（RPE）增殖，这对于适当的视裂闭合至关重要。在目标2中， 建议检查Nf 2破坏如何导致早期视杯中的RPE增殖延长。此外，本发明还提供了一种方法， 我们的初步数据显示，通过调节Hippo信号在眼内的早期作用， 眼周组织在目标3中，我们将分析雅普/Taz和Nf 2在早期视杯形成过程中的确切作用。 形态发生这里提出的研究将是理解细胞和 控制眼睛形态发生的分子机制，对于推进治疗和再生至关重要 眼部疾病的努力。