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Resolving the basis of phenotypically variable hereditary abnormalities of eye formation

解决眼睛形成的表型变异遗传异常的基础

基本信息

批准号：
MR/T020164/1
负责人：
Stephen Wilson
金额：
$ 200.19万
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：
2020
资助国家：
英国
起止时间：
2020 至无数据
项目状态：
未结题

来源：
https://gtr.ukri.org/projects?ref=MR%2FT020164%2F1
关键词：
Resolving basis phenotypically variable hereditary

项目摘要

Our eyes start out as outpocketings of brain tissue during early embryonic development. The cells destined to form the eyes originate within the neural plate, the precursor of the central nervous system. As the neural plate folds up to form the brain, the eye-forming cells bulge out laterally forming optic cups, the structures that later differentiate as eyes. Each optic cup undergoes shape changes and tissue fusion closes a gap (the optic fissure) present on one side of the cup, leading to formation of the intact globe shaped eye. The complex orchestration of cell movements that form the eyes is an example of morphogenesis - the process by which embryonic cells form into tissues and organs. Many of the genes that regulate the formation of the eye have yet to be identified. One reason that this lack of knowledge needs to be addressed is that congenital malformations of the eye, such as anophthalmia (lack of eyes), microphthalmia (small eyes) and coloboma (a failure in optic fissure fusion), being compatible with life and reproduction, are relatively common in the human population. As these are congenital defects, this means that eye problems are present from birth. While anophthalmic patients are blind, microphthalmic and coloboma patients can have severe visual impairment. For instance, colobomas are a common cause of visual problems, can cause retinal detachment and cataracts, and often lead to blindness.In this project, we will use zebrafish embryos to identify genes and genetic interactions important for eye formation. Zebrafish embryos are small, transparent and develop externally, facilitating the study of normal development and disease in the intact animal. Together with their amenability to genetic analysis, these features make fish embryos an excellent model system to study eye formation in normal and pathological conditions. Indeed, we can visualise all of the cells in the developing eye in living embryos both in healthy fish and in fish carrying one or more genetic mutations that compromise eye formation. Consequently, we can use research in fish both to identify those genes needed for eye formation and to understand the mechanisms by which such genes build functional eyes.Although some congenital abnormalities of eye formation are due to mutations in single genes, we suspect that in many cases, such defects are due to disruption of two or more genes. Consequently, in this project, we will use novel, powerful approaches that allow us to systematically analyse the consequences of simultaneous disrupted function of two or more genes that are candidates for causing eye defects when non-functional. To facilitate this research, our current MRC funding has enabled us to develop lines of fish carrying mutations that make the fish more likely to show eye phenoytpes when additional genes are disrupted. We will remove function of one or more additional genes in these "sensitised" fish lines to identify new genes and genetic interactions important for eye formation. We will also study the function of several genes that, when disrupted, give very similar eye defects both in fish and in humans as although we know these genes to be important, we do not understand how they function. Finally, we will study why individuals carrying the same genetic mutations can show quite different eye phenotypes. To facilitate this, we have lines of fish in which we can perform genetic or environmental perturbations that affect the severity of the eye defects. Overall, our research will help to bridge the gap between the highest quality research in model systems and human disease phenotypes. We will improve our understanding of normal eye development and will use new zebrafish models of human eye diseases to gain further insights into the causes of hereditary ocular malformations. Our research also has the potential to be of great value in the diagnosis of congenital abnormalities of eye formation.

我们的眼睛最初是胚胎发育早期脑组织的突出部分。注定形成眼睛的细胞起源于神经板，即中枢神经系统的前身。当神经板折叠形成大脑时，形成眼睛的细胞横向凸出形成视杯，这种结构后来分化为眼睛。每个视杯都会发生形状变化，组织融合会闭合视杯一侧的间隙（视裂），从而形成完整的球形眼睛。形成眼睛的细胞运动的复杂编排是形态发生的一个例子，形态发生是胚胎细胞形成组织和器官的过程。许多调节眼睛形成的基因尚未被识别。需要解决这种知识缺乏的原因之一是，先天性眼睛畸形，例如无眼症（缺乏眼睛）、小眼球症（小眼睛）和缺损（视裂融合失败），与生活和繁殖相适应，在人群中相对常见。由于这些都是先天性缺陷，这意味着眼睛问题从出生起就存在。无眼症患者是失明的，而小眼症和缺损患者可能有严重的视力障碍。例如，缺损是视觉问题的常见原因，可导致视网膜脱离和白内障，并常常导致失明。在这个项目中，我们将使用斑马鱼胚胎来识别对眼睛形成重要的基因和遗传相互作用。斑马鱼胚胎小、透明且在外部发育，有利于研究完整动物的正常发育和疾病。加上它们易于进行遗传分析，这些特征使鱼类胚胎成为研究正常和病理条件下眼睛形成的优秀模型系统。事实上，我们可以在健康的鱼和携带一种或多种损害眼睛形成的基因突变的鱼的活胚胎中观察到正在发育的眼睛中的所有细胞。因此，我们可以利用鱼类研究来识别眼睛形成所需的基因，并了解这些基因构建功能性眼睛的机制。虽然眼睛形成的一些先天性异常是由于单个基因的突变造成的，但我们怀疑在许多情况下，此类缺陷是由于两个或多个基因的破坏造成的。因此，在这个项目中，我们将使用新颖、强大的方法，使我们能够系统地分析两个或多个基因功能同时破坏的后果，这些基因是非功能时导致眼睛缺陷的候选基因。为了促进这项研究，我们目前的 MRC 资助使我们能够开发出携带突变的鱼类品系，这些突变使得当其他基因被破坏时，这些鱼更有可能表现出眼睛表型。我们将去除这些“敏感”鱼线中一个或多个附加基因的功能，以识别对眼睛形成重要的新基因和遗传相互作用。我们还将研究几个基因的功能，当这些基因被破坏时，它们会在鱼类和人类中产生非常相似的眼睛缺陷，因为尽管我们知道这些基因很重要，但我们不了解它们是如何发挥作用的。最后，我们将研究为什么携带相同基因突变的个体会表现出截然不同的眼睛表型。为了实现这一目标，我们可以对鱼线进行基因或环境扰动，从而影响眼睛缺陷的严重程度。总的来说，我们的研究将有助于弥合模型系统和人类疾病表型方面最高质量研究之间的差距。我们将增进对正常眼睛发育的了解，并将使用新的人类眼部疾病斑马鱼模型来进一步了解遗传性眼部畸形的原因。我们的研究在诊断先天性眼睛形成异常方面也具有巨大的价值。

项目成果

期刊论文数量（10）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

Foxd1-dependent induction of a temporal retinal character is required for visual function.

DOI：
10.1242/dev.200938
发表时间：
2022-12-15
期刊：
Development (Cambridge, England)
影响因子：
0
作者：
通讯作者：

A simple and effective F0 knockout method for rapid screening of behaviour and other complex phenotypes.

DOI：
10.7554/elife.59683
发表时间：
2021-01-08
期刊：
eLife
影响因子：
7.7
作者：
Kroll F;Powell GT;Ghosh M;Gestri G;Antinucci P;Hearn TJ;Tunbak H;Lim S;Dennis HW;Fernandez JM;Whitmore D;Dreosti E;Wilson SW;Hoffman EJ;Rihel J
通讯作者：
Rihel J

A versatile, automated and high-throughput drug screening platform for zebrafish embryos.

DOI：
10.1242/bio.058513
发表时间：
2021-09-15
期刊：
Biology open
影响因子：
2.4
作者：
Lubin A;Otterstrom J;Hoade Y;Bjedov I;Stead E;Whelan M;Gestri G;Paran Y;Payne E
通讯作者：
Payne E

Loss of slc39a14 causes simultaneous manganese hypersensitivity and deficiency in zebrafish.

SLC39A14的损失导致斑马鱼的同时锰超敏反应和缺乏。