Robustness in eye development: addressing the mechanisms behind eye formation and growth compensation

眼睛发育的稳健性：解决眼睛形成和生长补偿背后的机制

• 批准号: MR/X001067/1
• 负责人: Rodrigo Young
• 金额: $ 98.14万
• 依托单位: University College London
• 依托单位国家: 英国
• 项目类别: Research Grant
• 财政年份: 2023
• 资助国家: 英国
• 起止时间: 2023 至 无数据
• 项目状态: 未结题
• 来源: https://gtr.ukri.org/projects?ref=MR%2FX001067%2F1
• 关键词: Robustness; eye; development; addressing; mechanisms

The eye is made of diverse structures and cell types that enable light to be transformed into a nerve impulse that travels to the brain. Despite their complexity, eyes develop from the eye primordium, a single group of cells established during the third week of human gestation. These cells will bud apart laterally to form the two optic vesicles, which will keep growing independently and differentiate into the distinct cell types that make an eye.There are still many unanswered questions regarding eye formation, for example, why are some people born with smaller or no eyes? This project aims to answer this particular question by combining genetic analysis of patients that have developmental eye globe defects with research in zebrafish, this project aims to answer this particular question. Genes control embryo development, and when specific genes are impaired by mutations, people are born with morphological defects. Therefore, studying what goes wrong when genes are mutated provides information about their function. Knowing which genes are mutated in patients can help us understand how organs are formed and are also necessary for the development of therapies to prevent or cure disease. Currently, only 10% of patients born with anophthalmia (A, no eyes) or microphthalmia (M, very small eyes) can be genetically diagnosed with a single pathogenic mutation. For the rest, we do not know the responsible gene mutation, which limits both the possibility of appropriate medical care and of developing therapies.Humans and zebrafish eyes develop in a similar way, even using the same genes. Therefore, studying the genes that work in fish eye development is applicable to humans. In zebrafish, we can also mimic mutations found in patients and study their effects upon eye formation.I recently discovered that zebrafish mutants that develop an eye primordium with half the number of cells can continue growing until they reach the appropriate size due to a growth compensation mechanism. Hence, growth compensation can mask the effect of mutations, which could explain why it is difficult to find genes involved in eye defects. However, I also found that certain combinations of mutations can further impair eye formation leading to embryos with no eyes or with small underdeveloped eyes, like in human patients. The important question is: how can we identify more gene mutations that lead to eye formation defects?Building on my recent findings, and using tools I have generated, this project aims to: 1. Identify new gene mutations in patients with anophthalmia and microphthalmia.2. Validate mutations identified in anophthalmia and microphthalmia patients in zebrafish.3. Molecular and cell biological characterisation of validated genes and mutations.Overall, this project aims to identify new diagnostic genes for anophthalmic and microphthalmic patients, to enable appropriate genetic counselling, enhance our understanding of eye development, and set the grounds to generate new therapies.

眼睛是由不同的结构和细胞类型，使光能够转化为神经冲动，前往大脑。尽管它们很复杂，但眼睛是从眼原基发育而来的，眼原基是人类妊娠第三周建立的一组细胞。这些细胞会从侧面分裂形成两个视泡，它们会独立生长并分化成构成眼睛的不同细胞类型。关于眼睛的形成还有许多未解之谜，例如，为什么有些人天生眼睛较小或没有眼睛？该项目旨在通过将对患有发育性眼地球仪缺陷的患者的遗传分析与对斑马鱼的研究相结合来回答这个特定问题，该项目旨在回答这个特定问题。基因控制着胚胎发育，当特定基因因突变而受损时，人就会天生有形态缺陷。因此，研究基因突变时出现的问题可以提供有关其功能的信息。了解患者的哪些基因发生了突变，可以帮助我们了解器官是如何形成的，也是开发预防或治疗疾病的疗法所必需的。目前，只有10%的先天性无眼症（A，没有眼睛）或小眼症（M，非常小的眼睛）患者可以通过基因诊断出具有单一致病突变。至于其他的，我们不知道是哪种基因突变导致的，这限制了适当的医疗护理和开发治疗方法的可能性。人类和斑马鱼的眼睛以类似的方式发育，甚至使用相同的基因。因此，研究在鱼眼发育中起作用的基因适用于人类。在斑马鱼中，我们也可以模仿在患者中发现的突变，并研究它们对眼睛形成的影响。我最近发现，斑马鱼突变体的眼睛原基只有一半的细胞数量，但由于生长补偿机制，它们可以继续生长，直到达到适当的大小。因此，生长补偿可以掩盖突变的影响，这可以解释为什么很难找到与眼睛缺陷有关的基因。然而，我也发现某些突变的组合会进一步损害眼睛的形成，导致胚胎没有眼睛或眼睛发育不全，就像人类患者一样。重要的问题是：我们如何识别更多导致眼睛形成缺陷的基因突变？基于我最近的发现，并使用我所生成的工具，这个项目的目标是：1。确定无眼症和小眼症患者的新基因突变.在斑马鱼无眼症和小眼症患者中鉴定出的突变.验证基因和突变的分子和细胞生物学特征。总的来说，该项目旨在为无眼和小眼患者确定新的诊断基因，以便进行适当的遗传咨询，提高我们对眼睛发育的理解，并为产生新的治疗方法奠定基础。