Animal and cellular models of microphthalmia

Abstract

Microphthalmia is a rare developmental eye disorder affecting 1 in 7000 births. It is defined as a small (axial length ⩾2 standard deviations below the age-adjusted mean) underdeveloped eye, caused by disruption of ocular development through genetic or environmental factors in the first trimester of pregnancy. Clinical phenotypic heterogeneity exists amongst patients with varying levels of severity, and associated ocular and systemic features. Up to 11% of blind children are reported to have microphthalmia, yet currently no treatments are available. By identifying the aetiology of microphthalmia and understanding how the mechanisms of eye development are disrupted, we can gain a better understanding of the pathogenesis. Animal models, mainly mouse, zebrafish and Xenopus, have provided extensive information on the genetic regulation of oculogenesis, and how perturbation of these pathways leads to microphthalmia. However, differences exist between species, hence cellular models, such as patient-derived induced pluripotent stem cell (iPSC) optic vesicles, are now being used to provide greater insights into the human disease process. Progress in 3D cellular modelling techniques has enhanced the ability of researchers to study interactions of different cell types during eye development. Through improved molecular knowledge of microphthalmia, preventative or postnatal therapies may be developed, together with establishing genotype-phenotype correlations in order to provide patients with the appropriate prognosis, multidisciplinary care and informed genetic counselling. This review summarises some key discoveries from animal and cellular models of microphthalmia and discusses how innovative new models can be used to further our understanding in the future.

Plain language summary: Animal and Cellular Models of the Eye Disorder, Microphthalmia (Small Eye) Microphthalmia, meaning a small, underdeveloped eye, is a rare disorder that children are born with. Genetic changes or variations in the environment during the first 3 months of pregnancy can disrupt early development of the eye, resulting in microphthalmia. Up to 11% of blind children have microphthalmia, yet currently no treatments are available. By understanding the genes necessary for eye development, we can determine how disruption by genetic changes or environmental factors can cause this condition. This helps us understand why microphthalmia occurs, and ensure patients are provided with the appropriate clinical care and genetic counselling advice. Additionally, by understanding the causes of microphthalmia, researchers can develop treatments to prevent or reduce the severity of this condition. Animal models, particularly mice, zebrafish and frogs, which can also develop small eyes due to the same genetic/environmental changes, have helped us understand the genes which are important for eye development and can cause birth eye defects when disrupted. Studying a patient's own cells grown in the laboratory can further help researchers understand how changes in genes affect their function. Both animal and cellular models can be used to develop and test new drugs, which could provide treatment options for patients living with microphthalmia. This review summarises the key discoveries from animal and cellular models of microphthalmia and discusses how innovative new models can be used to further our understanding in the future.

Keywords: Xenopus; cells; development; eye; human; iPSC; microphthalmia; mouse; optic vesicles; organoids; zebrafish.

Figure 1.

Diagrams of mature eye structure in human, mouse, zebrafish and Xenopus, and images of microphthalmic eyes in human and zebrafish. (a) Human eye with a cone-rich macula responsible for central vision, and a small lens which refracts light, along with the cornea. (b) Mouse eye with an enlarged lens compared with humans and lacking a cone-rich macula, with cones instead dispersed throughout the retina. (c) Zebrafish eye with thick neural retina layer and spherical lens which alone is responsible for focusing light. (d) Xenopus eye with a large, spherical lens encompassing most of the vitreous. (e) Clinical image of patient with unilateral left microphthalmia with and without prosthetic shell. (f) Wildtype and microphthalmic zebrafish at 76 h post fertilisation (hpf).

Figure 2.

Genes identified to cause microphthalmia in mouse, zebrafish and humans based on database and literature search, with overlapping genes listed. Mouse data from Mouse Genome Informatics database (http://www.informatics.jax.org/). Zebrafish data from Zebrafish Information Network (ZFIN) database (https://zfin.org/). Data from December 2020. Full list of genes in Supplemental Table 1.