Anterior segment dysgenesis (ASD) encompasses a variety of developmental disorders of ocular anterior segment morphogenesis, a complex process involving several cell lineages and their associated extracellular matrix (ECM). The contribution of ECM remodeling to anterior segment morphogenesis has not been the subject of prior investigation. We recently discovered that loss of a single Adamts9 allele (encoding a secreted metalloprotease) resulted in Peters anomaly (corneal leukoma and persistent lens stalk) and lens defects, including cataract. ADAMTS9 is likely a major substrate for the glucosyltransferase B3GALTL, which is mutated in human Peters plus syndrome (PPS). In PPS, extraocular birth defects, including cleft palate and cardiac development anomalies, in which ADAMTS9 had been previously implicated, accompany Peters anomaly. We hypothesize that ADAMTS9 secreted by endothelial cells of the hyaloid vasculature and by the optic cup, is required for ECM turnover and could act non-autonomously on the lens and neural crest cells to regulate anterior segment morphogenesis. ADAMTS9 cleaves the proteoglycan, versican, about which little is known during eye development, despite its role in eye disease (Wagner syndrome). Also, preliminary studies support investigation of the ECM molecules, fibronectin and fibrillin-2 as potential ADAMTS9 substrates.
In aim 1 of this proposal, we will comprehensively characterize ADAMTS9 modification by B3GALTL in vitro, and the consequences of preventing this modification in cultured cells. We will define the developmental, cellular and molecular changes underlying ASD resulting from Adamts9 haploinsufficiency.
In aim 2, we will use a new floxed Adamts9 allele for conditional inactivation in vascular endothelium (Tie2-Cre), and optic cup (?re), to delineate how ADAMTS9 expressed by these specific lineages drives anterior segment morphogenesis. We will specifically investigate whether ADAMTS9 interacts with and proteolytically processes versican, fibronectin, and fibrillin-2, both in vitro and in the eye. Together, these aims provide a mechanistic continuum from B3GALTL to fundamentals of eye development to molecular actions of ADAMTS9. Relevance to public health: ADAMTS9 is a novel candidate gene for Peters anomaly, PPS or its variants, and other forms of human ASD and/or congenital cataract for which causative gene mutations are unknown. It will provide answers to a hitherto ignored question, i.e. how does ECM dynamics influence early eye development and what are the key proteases that modify the ECM? It will advance fundamental knowledge of ocular and lens morphogenesis that is highly relevant to ASD, childhood glaucoma and cataract, and provides mechanisms pertinent to the formation and possibly, the prevention of adult glaucoma and cataracts.

Public Health Relevance

This proposal will determine novel mechanisms that contribute to development of the front of the eye (the anterior segment), which includes the lens. When anterior segment structures, such as the lens and cornea develop incorrectly in the embryo, sight can be permanently impaired at birth or in childhood, in part because the visual center in the brain needs proper stimulus to develop, and because problems with the front of the eye can indirectly damage the retina and optic nerve by leading to high back-pressure (glaucoma). The proposal investigates a new gene defect we have discovered in mice (in a gene named ADAMTS9) that causes an eye abnormality very similar to that found in human eye defects (Peters anomaly and Peters plus syndrome) that includes a type of cataract and glaucoma.

National Institute of Health (NIH)
National Eye Institute (NEI)
Research Project (R01)
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Special Emphasis Panel (BVS)
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Araj, Houmam H
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Cleveland Clinic Lerner
Other Basic Sciences
Schools of Medicine
United States
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Hendee, Kathryn; Wang, Lauren Weiping; Reis, Linda M et al. (2017) Identification and functional analysis of an ADAMTSL1 variant associated with a complex phenotype including congenital glaucoma, craniofacial, and other systemic features in a three-generation human pedigree. Hum Mutat 38:1485-1490
Dubail, Johanne; Vasudevan, Deepika; Wang, Lauren W et al. (2016) Impaired ADAMTS9 secretion: A potential mechanism for eye defects in Peters Plus Syndrome. Sci Rep 6:33974
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