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Review
. 2019 Aug 14;7(3):16.
doi: 10.3390/jdb7030016.

The Molecular Basis of Human Anophthalmia and Microphthalmia

Philippa Harding  1 , Mariya Moosajee  2   3   4
Affiliations
Review

The Molecular Basis of Human Anophthalmia and Microphthalmia

Philippa Harding et al. J Dev Biol. .

"VSports注册入口" Abstract

Human eye development is coordinated through an extensive network of genetic signalling pathways VSports手机版. Disruption of key regulatory genes in the early stages of eye development can result in aborted eye formation, resulting in an absent eye (anophthalmia) or a small underdeveloped eye (microphthalmia) phenotype. Anophthalmia and microphthalmia (AM) are part of the same clinical spectrum and have high genetic heterogeneity, with >90 identified associated genes. By understanding the roles of these genes in development, including their temporal expression, the phenotypic variation associated with AM can be better understood, improving diagnosis and management. This review describes the genetic and structural basis of eye development, focusing on the function of key genes known to be associated with AM. In addition, we highlight some promising avenues of research involving multiomic approaches and disease modelling with induced pluripotent stem cell (iPSC) technology, which will aid in developing novel therapies. .

Keywords: OTX2; SOX2; anophthalmia; coloboma; development; eye; genes; genetics; induced pluripotent stem cells; microphthalmia. V体育安卓版.

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Conflict of interest statement

The authors declare no conflict of interest.

Figures

Figure 1
Figure 1
Clinical images of anophthalmia and microphthalmia. (a) Bilateral anophthalmia. (b) Bilateral microphthalmia. (c) Unilateral anophthalmia with shell.
Figure 2
Figure 2
The genetics of early optic vesicle development. (a) A single eye field is induced at the midline of the anterior neural plate, through OTX2 and SOX2 coregulation of RAX, along with SIX3-mediated repression of WNT, which allows upregulation of eye field transcription factors (EFTFs) including PAX6, RAX, LHX2, TBX3 and SIX6. (b) The eye field is formed expressing EFTFs, which form a self-regulating network sufficient to coordinate the development of the eye through suppression of genes that antagonize eye development and upregulation of genes required for eye development. (c) Secretion of factors from TGFβ, FGF and SHH families from the underlying axial mesoderm stimulate the anterior migration of prospective hypothalamic cells, causing the eye field to split in two to form bilateral optic primordia. (d) Cellular proliferation and bilateral migration of the optic primordia is regulated by RAX. (e) The optic primordia evaginate from the forebrain through the cephalic mesenchyme forming bilateral optic pits/grooves. (f) Extended evagination of the optic pits through the cephalic mesenchyme results in the formation of bilateral optic vesicles.
Figure 3
Figure 3
The genetics of optic cup and lens formation. (a) A preplacodal region develops within the surface ectoderm overlying the optic pit/groove, stimulated by expression of SIX3, which activates PAX6 and SOX2. (b) The lens placode is signalled to thicken through LHX2-regulated BMP4 expression from the evaginating optic vesicle. (c) The developing lens placode releases BMP and retinoic acid (RA), which bind to the optic vesicle, stimulating coordinated invagination of the optic vesicle and lens placode, which forms the lens pit. (d) The invagination of the optic vesicle results in the formation of a bilayered optic cup. (e) TGFβ signalling from the extraocular mesenchyme induces and maintains MITF and OTX2 expression in the outer layer of the optic cup, which forms the presumptive retinal pigmented epithelium (RPE). FGF signals from the surface ectoderm stimulate the inner layer of the optic cup to form a VSX2-expressing presumptive neural retina (NR). The continued invagination of the lens pit results in the formation of the lens vesicle. (f) From 47 days gestation, retinal differentiation occurs, with the inner layer of the optic cup forming the neural retina (NR) and the outer layer forming the retinal pigmented epithelium (RPE). The lens vesicle detaches from the surface ectoderm and forms a definitive lens by 58 days gestation.
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