Building the developmental oculome: systems biology in vertebrate eye development and disease

Abstract

The vertebrate eye is a sophisticated multi-component organ that has been actively studied for over a century, resulting in the identification of the major embryonic and molecular events involved in its complex developmental program. Data gathered so far provides sufficient information to construct a rudimentary network of the various signaling molecules, transcription factors and their targets for several key stages of this process. With the advent of genomic technologies, there has been a rapid expansion in our ability to collect and process biological information, and the use of systems-level approaches to study specific aspects of vertebrate eye development has already commenced. This is beginning to result in the definition of the dynamic developmental networks that operate in ocular tissues, and the interactions of such networks between coordinately developing ocular tissues. Such an integrative understanding of the eye by a comprehensive systems-level analysis can be termed the “oculome”, and that of serial developmental stages of the eye as it transits from its initiation to a fully formed functional organ represents the “developmental oculome”. Construction of the developmental oculome will allow novel mechanistic insights that are essential for organ regeneration-based therapeutic applications, and the generation of computational models for eye disease states to predict the effects of drugs. This review discusses our present understanding of two of the individual components of the developing vertebrate eye – the lens and retina – at both the molecular and systems levels, and outlines the directions and tools required for construction of the developmental oculome.

Compound mouse mutants of bZIP transcription factors Mafg and Mafk reveal a regulatory network of non-crystallin genes associated with cataract

“…The ocular lens is a transparent tissue that functions to focus light on the retina, and is essential for high-resolution vision (Lachke and Maas 2010; Bassnett et al 2011). Loss of lens transparency results in an eye defect termed cataract, which is the leading cause of visual impairment worldwide (Shiels et al 2010).…”

“…In contrast to the detailed understanding of the transcriptional circuitry that functions in early mammalian lens development and in the maintenance of anterior epithelial cells, our understanding of transcription factors that function in lens fiber cells is markedly limited (Lachke and Maas 2010; Cvekl and Ashery-Padan 2014). Besides Pax6, studies on human patients or mouse models have identified only seven other transcription factors – Prox1, Sox1, ATF4/CREB2, Pitx3, Gata3, Hsf4 and the large Maf family member, Maf (also called c-Maf) – that function to regulate gene expression in differentiating fiber cells (Donner et al 2007; Tanaka et al 1998; Kim et al 1999; Kawauchi et al 1999; Ring et al 2000; Jamieson et al 2002; Nishiguchi et al 1998; Wigle et al 1999; Bu et al 2002; Fujimoto et al 2004; Maeda et al 2009; Shaham et al 2009; Sorokina et al 2011).…”

Homozygous null mutation in ODZ3 causes microphthalmia in humans

“…As a result of the crosstalk between these structures, the optic vesicle morphs into the adult retina and the lens placode gives rise to the structures of the anterior segment of eye, most notably the lens and cornea. [1][2][3][4][5] Perturbation of this precisely controlled and highly conserved developmental process can result in a wide array of clinical phenotypes, but microphthalmia (small eye) is the prototypic phenotypic consequence of arrested or impaired early development of the eye (the term "anophthalmia" is used when the eye globe fails to develop completely). 6 Microphthalmia can accompany numerous syndromes, but the majority of microphthalmia patients are nonsyndromic.…”

Roles of the 15-kDa Selenoprotein (Sep15) in Redox Homeostasis and Cataract Development Revealed by the Analysis of Sep 15 Knockout Mice

“…A prominent human disease associated with altered protein folding is cataract formation, with opacities caused by aggregation of lens structural proteins such as ␣-crystallins. It has been proposed that genes that are expressed in a lens-enriched manner in the developing mouse lens may have a functional role in the development and maintenance of lens transparency and, therefore, may represent candidate genes for cataract formation (32). In this approach, lens enrichment of a candidate gene is scored against its expression in whole embryonic tissues at various stages in development 3 This approach has been successful in identifying cataract loci (33).…”