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

眼睛由不同的结构和细胞类型组成，这些结构和细胞类型使光线能够转化为神经冲动，并传递到大脑。尽管眼睛很复杂，但眼睛是从眼睛原基发育而来的，眼睛原基是在人类怀孕第三周形成的一组细胞。这些细胞会侧向分裂，形成两个视泡，它们将继续独立生长并分化为不同类型的细胞，形成眼睛。关于眼睛的形成，仍然有许多悬而未决的问题，例如，为什么有些人出生时眼睛较小或没有眼睛？这个项目旨在通过结合对患有发育性眼球缺陷的患者的基因分析和对斑马鱼的研究来回答这个特殊的问题。基因控制胚胎发育，当特定基因因突变而受损时，人们出生时就会有形态缺陷。因此，研究基因突变时出了什么问题，可以提供有关基因功能的信息。了解患者体内哪些基因发生突变可以帮助我们了解器官是如何形成的，也是开发预防或治愈疾病的治疗方法所必需的。目前，只有10%的出生时患有无眼症(A，无眼)或小眼炎(M，非常小的眼睛)的患者可以被基因诊断为单一致病突变。对于其余的人，我们不知道负责的基因突变，这限制了适当的医疗保健和开发治疗的可能性。人类和斑马鱼的眼睛发育方式相似，即使使用相同的基因。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身上发现的突变，并研究它们对眼睛形成的影响。我最近发现，由于生长补偿机制，发育出眼睛原基的斑马鱼突变体可以继续生长，直到它们达到合适的大小。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部结构缺陷的基因突变？基于我最近的发现，并使用我生成的工具，该项目旨在：1.在无眼症和小眼球患者中识别新的基因突变。验证斑马鱼无眼症和小眼球症患者中发现的突变。分子和细胞生物学特性验证的基因和突变。总体而言，该项目旨在为无眼症和小眼症患者识别新的诊断基因，以便进行适当的遗传咨询，增强我们对眼睛发育的了解，并为开发新的治疗方法奠定基础。

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.