In 2017, 253 million people were visually impaired worldwide; 217 million of them had amblyopia, whereas 36 million of them were blind. 8,47 The prevalence of anophthalmia, a birth defect whereby a baby is born absent one or both its eyes, ranges from 0.6 to 4.2 per 100,000 births. 33,41 Absence of neural activity in the visual system of humans and mice with anophthalmia leads to a reductions in optic radiation, the lateral geniculate nucleus, and primary visual cortex due to cross-modal plasticity. 28 Because circadian rhythmicity is synchronized by the light-dark cycle, loss of sensory input from the retina due to anophthalmia leads to abnormal circadian rhythmicity in the absence of retinohypothalamic projection and a neural pathway to the pineal gland. 3 Studying the relationship between cross-modal rewiring and circadian rhythmicity in anophthalmic animal models is an important way for us to understand the degree of neural plasticity that animals experience during profound blindness and changes to behavior which inevitably occur.More than 80 genes are associated with microphthalmia, anophthalmia, and coloboma (MAC). These genes are categorized into 4 groups, depending on the effects expressed. The largest of these groups comprises genes related to transcription; TGFβ-BMP signal molecules and retinoic acid pathway members are assigned to another 2 groups. The remaining genes are assigned to the last group. 37 Clinical findings indicate that mutations of these MAC-related genes are associated with syndromic microphthalmia, anophthalmia, and coloboma, including abnormalities in ocular development, in sclerocornea and corneal opacity, as well as endocrine regulation. 31,42,43 For example, mutation of SOX2, OTX2, STRA6, BMP4, HCCS, or PORCN causes abnormal regulation of the endocrine system, leading to growth retardation. 42 To increase the value of animal modeling, it is essential to understand how genetic mutations are being expressed in the species used.The simulation of human disease in animal models involves adopting animals with congenital or induced pathologies that are similar to those in humans for biomedical and behavioral testing and observation. The results of such testing and observation help inform the development of human treatments. 24,39,45 Developing suitable animal models is key to successful basic medical research. This process includes the selection of an appropriate animal species for modeling human afflictions. For example, although mice and rats are often used in animal models, they are considerably different from humans in terms of physiology, anatomy, and behavior patterns during the light-dark cycle. 14 Because most mice and rats are nocturnal animals, their use in simulating abnormal circadian rhythms in humans and diurnal animals is not optimal. 14 In contrast, pigs (Sus scrofa) are highly suited to simulating human circadian rhythmicity and for ocular developmental research. 17,20,22,39,40 Many animal models have been developed for eye disease studies. Zebrafish with congenital genet...