The overall goal of this proposal is to identify novel genes and associated pathways involved in the development of the anterior segment. Genetic studies have contributed a great deal to our current understanding of the developmental processes as well as associated genes and pathways during the ocular development. However, many genes as well as molecular mechanisms are still unclear. To aid in the discovery of the gene/pathway/mechanism associated with anterior segment development, phenotype driven approaches have been utilized extensively. This proposal focuses on the woe and woe2 mouse models. Both woe and woe2 are autosomal recessive loci that exhibit the eyelid open at birth (EOB) phenotype, microphthalmia/anopthalmia, cataracts and defects in the anterior segment structures originating from the neural crest (NC) cells. The woe2 mice unlike woe exhibit optic nerve hypoplasia. Both mice exhibit the wavy fur phenotype. Based on the phenotypic similarities, we hypothesized that woe and woe2 genes play a role in overlapping molecular pathways essential for ocular development. By applying the positional cloning strategies we identified genes and mutations responsible for woe and woe2. The woe mice carry a hypomorphic mutation in the Adam17 gene whereas the woe2 mice carry a deletion in the Ppp1r13l gene. The goal of this proposal is to understand the role of Adam17 and Ppp1r13l during the eye development.
The Specific Aim 1 focuses on evaluation of Adam17 role during the embryonic eyelid closure, development of NC-derived anterior structures and a role of Adam17 during corneal wound healing.
The Specific Aim2 focuses on evaluation of the role of Ppp1r13l during embryonic eyelid closure, anterior segment development and the role of Ppp1r13l during optic nerve development. This approach will provide novel information about the functions of Adam17 and Ppp1r13l and the associated pathways during anterior segment development.

Public Health Relevance

This proposal focuses on the identification of novel regulatory genes and the pathways governing the anterior segment development. In order to better understand the etiology of common anterior segment eye diseases such as cataracts and glaucoma, it is essential that we gain a better understanding about the mechanisms that play a central role during development.

National Institute of Health (NIH)
National Eye Institute (NEI)
Research Project (R01)
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Study Section
Anterior Eye Disease Study Section (AED)
Program Officer
Chin, Hemin R
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Medical College of Wisconsin
Anatomy/Cell Biology
Schools of Medicine
United States
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Lange, Philip T; Darrah, Eric J; Vonderhaar, Emily P et al. (2016) Type I Interferon Counteracts Antiviral Effects of Statins in the Context of Gammaherpesvirus Infection. J Virol 90:3342-54
Handley, Mark T; Carpanini, Sarah M; Mali, Girish R et al. (2015) Warburg Micro syndrome is caused by RAB18 deficiency or dysregulation. Open Biol 5:150047
Park, Anna Kyunglim; Liegel, Ryan P; Ronchetti, Adam et al. (2014) Targeted disruption of Tbc1d20 with zinc-finger nucleases causes cataracts and testicular abnormalities in mice. BMC Genet 15:135
Liegel, Ryan P; Ronchetti, Adam; Sidjanin, D J (2014) Alkylglycerone phosphate synthase (AGPS) deficient mice: models for rhizomelic chondrodysplasia punctate type 3 (RCDP3) malformation syndrome. Mol Genet Metab Rep 1:299-311
Hassemer, Eryn L; Endres, Bradley; Toonen, Joseph A et al. (2013) ADAM17 transactivates EGFR signaling during embryonic eyelid closure. Invest Ophthalmol Vis Sci 54:132-40
Liegel, Ryan P; Handley, Mark T; Ronchetti, Adam et al. (2013) Loss-of-function mutations in TBC1D20 cause cataracts and male infertility in blind sterile mice and Warburg micro syndrome in humans. Am J Hum Genet 93:1001-14
Merath, Kate; Ronchetti, Adam; Sidjanin, Duska J (2013) Functional analysis of HSF4 mutations found in patients with autosomal recessive congenital cataracts. Invest Ophthalmol Vis Sci 54:6646-54
Toonen, Joseph; Liang, Lina; Sidjanin, Duska J (2012) Waved with open eyelids 2 (woe2) is a novel spontaneous mouse mutation in the protein phosphatase 1, regulatory (inhibitor) subunit 13 like (Ppp1r13l) gene. BMC Genet 13:76
Liegel, R; Chang, B; Dubielzig, R et al. (2011) Blind sterile 2 (bs2), a hypomorphic mutation in Agps, results in cataracts and male sterility in mice. Mol Genet Metab 103:51-9
Merath, Kate M; Chang, Bo; Dubielzig, Richard et al. (2011) A spontaneous mutation in Srebf2 leads to cataracts and persistent skin wounds in the lens opacity 13 (lop13) mouse. Mamm Genome 22:661-73

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