Morphogenesis and growth of the eye in health and disease

虽然我们的眼睛与我们的大脑有着非常不同的外观，但它们起源于早期胚胎发育期间脑组织的外囊。注定要形成眼睛的神经上皮组织最初是神经板内的一组连贯的细胞，神经板是中枢神经系统的前体。当神经板折叠起来形成大脑和脊髓时，视野细胞向左右两侧凸出，形成两只眼睛。每只眼睛在形成时都会经历戏剧性的形状变化。这些包括组织融合，其闭合存在于眼睛一侧的裂隙（脉络膜裂隙），并导致形成完整的地球仪。形成眼睛所需的细胞运动的复杂协调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。人们对调节眼睛规格和形态发生的基因以及伴随眼睛形成的细胞和组织行为知之甚少。需要解决这种知识缺乏的原因之一是，先天性眼部畸形，如无眼症，小眼症和缺损，在人类中相对常见，可导致严重的视力障碍或更严重的颅面表型。例如，脉络膜裂不能闭合导致眼缺损，这包括一组常见的眼缺陷，影响所有年龄段的人，但尤其是幼儿。缺损通常是先天性疾病，通过检测眼睛任何结构（包括角膜、视网膜和视神经）中的缺口、间隙、孔或裂缝来诊断。这些病理是视力问题的常见原因，可导致视网膜脱离和白内障，并经常导致受影响患者失明。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，并观察伴随这一过程各个阶段的细胞行为。斑马鱼胚胎小，透明，外部发育，有利于研究完整动物的正常发育和疾病。再加上它们对遗传分析的顺从性，这些特征使鱼胚胎成为研究正常和病理条件下眼睛形成的极好模型系统。事实上，高度复杂的成像技术使我们能够可视化活体斑马鱼胚胎中发育中眼睛的所有细胞。与此同时，我们已经产生了一个新的家庭的鱼，产生后代表现出各种缺陷，包括缺乏眼睛，异常形态和coloboma。我们将确定在家庭的眼睛缺陷的鱼的基因突变，这将使我们了解基因和遗传途径，调节正常的眼睛形成。这些基因的人类版本是突变时导致先天性眼睛异常的候选者，因此，我们将与合作者一起筛选眼睛缺陷患者的基因突变。由于眼睛缺陷通常是由一个以上基因的功能缺陷引起的，我们的目标之一是研究与眼睛形成有关的基因对之间的遗传相互作用。在基因鉴定的同时，我们将研究伴随眼睛形成的细胞和组织运动，以了解这一复杂过程的机制基础。随着我们的理解的增加，我们将能够使用获得的知识来解决为什么先天性眼睛缺陷会在某些基因不正常的情况下出现。总体而言，我们的研究将有助于弥合模型系统和人类疾病表型的最高质量基础研究之间的差距。这些分析将使我们能够建立人类眼病的新模型，并使我们能够进一步了解正常的眼睛发育和遗传性眼部畸形的原因。

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.