Morphogenesis and growth of the eye in health and disease

健康和疾病中眼睛的形态发生和生长

基本信息

批准号：
MR/L003775/1
负责人：
Stephen Wilson
金额：
$ 226.81万
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：
2014
资助国家：
英国
起止时间：
2014 至无数据
项目状态：
已结题

来源：
https://gtr.ukri.org/projects?ref=MR%2FL003775%2F1
关键词：
Morphogenesis growth eye health disease

项目摘要

Although our eyes have a very different appearance to our brain, they originate as outpocketings of brain tissue during early embryonic development. The neuroepithelial tissue destined to form the eyes is initially a coherent group of cells within the neural plate, the precursor of the central nervous system. As the neural plate folds up to form the brain and spinal cord, the eyefield cells bulge out laterally to the left and right to form the two eyes. Each eye undergoes dramatic shape changes as it forms. These include a tissue fusion that closes a fissure present on one side of the eye (the choroid fissure), and leads to the formation of the intact globe of the eye. The complex orchestration of cell movements required to form the eyes is an example of tissue morphogenesis - the process by which embryonic cells form into tissues and organs. The genes that regulate the specification and morphogenesis of the eye and the cell and tissue behaviours that accompany eye formation are poorly understood. One of the reasons that this lack of knowledge needs to be addressed is that congenital malformations of the eye, such as anophthalmia, microphthalmia and coloboma, are relatively common in humans and can cause severe visual impairment or more severe craniofacial phenotypes. For instance the failure of the choroid fissure to close results in eye colobomas that encompass a group of common eye defects affecting people of all ages, but especially young children. Colobomas are usually congenital conditions diagnosed by detection of a notch, gap, hole or fissure in any of the structures of the eye, including the cornea, retina and optic nerve. These pathologies are a common cause of visual problems, can cause retinal detachment and cataracts and often lead to blindness in affected patients. In this project, we will use zebrafish embryos to identify genes important for eye formation and to characterise the cell behaviours that accompany various stages of this process. 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, highly sophisticated imaging techniques allow us to visualise all of the cells in the developing eye in the living zebrafish embryo. Coupled with this, we have generated a novel collection of families of fish that give rise to progeny exhibiting a variety of defects including absence of the eyes, abnormal morphogenesis and coloboma.We will identify the genetic mutations in the families of fish with eye defects and this will give us insights into the genes and genetic pathways that regulate normal eye formation. The human versions of these genes are candidates for causing congenital eye abnormalities when mutated and so, with collaborators, we will screen patients with eye defects for mutations in the genes. As eye defects often arise as a consequence of defective function of more than one gene, one of our aims will be to look at the genetic interactions between pairs of genes implicated in eye formation. In parallel to the gene identification, we will characterise the cell and tissue movements that accompany eye formation to gain an understanding of the mechanistic bases of this complex process. As our understanding increases, we will then be able to use the acquired knowledge to resolve why the congenital eye defects arise when certain genes are not functioning correctly.Overall, our research will help to bridge the gap between the highest quality basic research in model systems and human disease phenotypes. These analyses will enable us to establish new models for human eye diseases and will allow us to gain further insight into normal eye development and into the causes of hereditary ocular malformations.

尽管我们的眼睛对我们的大脑外观截然不同，但它们在早期胚胎发育过程中起源于脑组织的伸出。最初，注定要形成眼睛的神经上皮组织是神经板中的一组连贯的细胞，这是中枢神经系统的前体。当神经板折叠以形成大脑和脊髓时，ekefield细胞向左和右侧侧面凸起，形成两只眼睛。每只眼睛都会在形成时会发生戏剧性的形状。这些包括组织融合，该组织融合了眼睛一侧（脉络裂）的裂缝，并导致眼睛完整地球的形成。形成眼睛所需的细胞运动的复杂编排是组织形态发生的一个例子 - 胚胎细胞形成组织和器官的过程。对眼睛形成的细胞和细胞和组织行为的调节的基因以及形成的细胞和组织行为的理解很少。缺乏知识需要解决的原因之一是，眼睛的先天性畸形，例如消性症，微观恐惧症和古生物瘤，在人类中相对常见，并且可能导致严重的视力障碍或更严重的颅面表型。例如，脉络膜裂缝未能关闭眼睛的果实，涵盖了一群影响所有年龄段的人，尤其是幼儿的常见眼睛缺陷。古罗巴马通常是通过检测到眼睛的任何结构（包括角膜，视网膜和视神经）的凹口，间隙，孔或裂缝诊断的先天性疾病。这些病理是视觉问题的常见原因，可能导致视网膜脱离和白内障，并且经常导致患者失明。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，并表征伴随该过程各个阶段的细胞行为。斑马鱼胚胎小，透明，并在外部发展，可促进完整动物的正常发育和疾病的研究。这些特征将其对遗传分析的敏感性，使鱼类胚胎成为在正常和病理条件下研究眼睛形成的极好模型系统。确实，高度复杂的成像技术使我们能够可视化活斑马鱼胚胎中发育中的所有细胞。再加上这一点，我们产生了一系列新型的鱼家族，引起后代，表现出各种缺陷，包括眼睛缺乏，异常形态发生和coloboma。我们将确定鱼类缺陷的鱼家族中的遗传突变，这将使我们对调节正常眼睛形成的基因和遗传途径的见解。这些基因的人类版本是突变时引起先天性眼异常的候选者，因此，与合作者一起，我们将筛选患有眼缺陷的基因突变的患者。由于多个基因的功能有缺陷，因此眼睛缺陷通常出现，我们的目标之一是查看与眼睛形成有关的基因对之间的遗传相互作用。与基因鉴定并行，我们将表征伴随眼睛形成的细胞和组织运动，以了解该复杂过程的机械碱基。随着我们的理解的提高，我们将能够利用获得的知识来解决为什么当某些基因无法正常运行时会出现先天性眼缺陷的原因。这些分析将使我们能够为人眼疾病建立新的模型，并使我们能够进一步了解正常的眼睛发育和遗传性眼畸形的原因。

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）

Cell Behaviors during Closure of the Choroid Fissure in the Developing Eye.

DOI：
10.3389/fncel.2018.00042
发表时间：
2018
期刊：
Frontiers in cellular neuroscience
影响因子：
5.3
作者：
Gestri G;Bazin-Lopez N;Scholes C;Wilson SW
通讯作者：
Wilson SW

NRP1 Regulates CDC42 Activation to Promote Filopodia Formation in Endothelial Tip Cells.

DOI：
10.1016/j.celrep.2015.05.018
发表时间：
2015-06-16
期刊：
Cell reports
影响因子：
8.8
作者：
Fantin A;Lampropoulou A;Gestri G;Raimondi C;Senatore V;Zachary I;Ruhrberg C
通讯作者：
Ruhrberg C

Cdon acts as a Hedgehog decoy receptor during proximal-distal patterning of the optic vesicle.

DOI：
10.1038/ncomms5272
发表时间：
2014-07-08
期刊：
NATURE COMMUNICATIONS
影响因子：
16.6
作者：
Julian Cardozo, Marcos;Sanchez-Arrones, Luisa;Sandonis, Africa;Sanchez-Camacho, Cristina;Gestri, Gaia;Wilson, Stephen W.;Guerrero, Isabel;Bovolenta, Paola
通讯作者：
Bovolenta, Paola

Opposing Shh and Fgf signals initiate nasotemporal patterning of the zebrafish retina.

DOI：
10.1242/dev.125120
发表时间：
2015-11-15
期刊：
Development (Cambridge, England)
影响因子：
0
作者：
Hernández-Bejarano M;Gestri G;Spawls L;Nieto-López F;Picker A;Tada M;Brand M;Bovolenta P;Wilson SW;Cavodeassi F
通讯作者：
Cavodeassi F

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