Critical functions for ocular gap junctions have been elucidated by the discovery of cataract causing mutations in human lens connexin genes. Since the lens is an avascular cyst, gap junction channels allow cells in the interior of the organ to gain access to metabolites absorbed at the surface from the aqueous humor. This metabolite exchange maintains the precise intracellular ionic conditions necessary to prevent precipitation of the crystallins and subsequent cataract formation. This idea is further supported by the observation that mice with targeted deletions of lens connexins also develop cataracts, thus providing animal models for the human pathology. One of the most difficult remaining challenges is to uncover the mechanisms whereby connexin gene disruption leads to pathological changes and vision loss. The long term goal of this application is to precisely define which cellular functions require gap junctional communication and to understand how the diversity in gap junctional structural proteins influences intercellular communication in ocular tissues. Experiments are outlined which are designed to explore why the elimination of connexin diversity, but not intercellular communication, leads to microphthalmia and cataracts in connexin50 (Cx50) knockout mice. In a second specific aim, experiments are designed to utilize transgenic technology to eliminate multiple connexins in the lens, so that lens development and function in the absence of gap junctional communication pathways can be studied. In a third aim, the generation of 'knock-in' animals where one connexin has been replaced by another is proposed to discriminate whether phenotypes result simply from differential decreases in the absolute numbers of intercellular channels in the different knockout models, rather than a loss of connexin diversity. In a final aim, Connexin diversity in the retina will be explored by functionally analyzing an entirely new class of connexin genes that are preferentially expressed in retinal neurons.

National Institute of Health (NIH)
National Eye Institute (NEI)
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Visual Sciences A Study Section (VISA)
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Liberman, Ellen S
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State University New York Stony Brook
Schools of Medicine
Stony Brook
United States
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Youssefian, Leila; Vahidnezhad, Hassan; Saeidian, Amir Hossein et al. (2018) A novel autosomal recessive GJB2-associated disorder: Ichthyosis follicularis, bilateral severe sensorineural hearing loss, and punctate palmoplantar keratoderma. Hum Mutat :
Srinivas, Miduturu; Verselis, Vytas K; White, Thomas W (2018) Human diseases associated with connexin mutations. Biochim Biophys Acta Biomembr 1860:192-201
Hu, Zhengping; Shi, Wen; Riquelme, Manuel A et al. (2017) Connexin 50 Functions as an Adhesive Molecule and Promotes Lens Cell Differentiation. Sci Rep 7:5298
Sellitto, Caterina; Li, Leping; Vaghefi, Ehsan et al. (2016) The Phosphoinosotide 3-Kinase Catalytic Subunit p110? is Required for Normal Lens Growth. Invest Ophthalmol Vis Sci 57:3145-51
Shi, Qian; Gu, Sumin; Yu, X Sean et al. (2015) Connexin Controls Cell-Cycle Exit and Cell Differentiation by Directly Promoting Cytosolic Localization and Degradation of E3 Ligase Skp2. Dev Cell 35:483-96
Gao, Junyuan; Sun, Xiurong; White, Thomas W et al. (2015) Feedback Regulation of Intracellular Hydrostatic Pressure in Surface Cells of the Lens. Biophys J 109:1830-9
Martinez, Jennifer M; Wang, Hong-Zhan; Lin, Richard Z et al. (2015) Differential regulation of Connexin50 and Connexin46 by PI3K signaling. FEBS Lett 589:1340-5
Rubinos, Clio; Villone, Krista; Mhaske, Pallavi V et al. (2014) Functional effects of Cx50 mutations associated with congenital cataracts. Am J Physiol Cell Physiol 306:C212-20
Slavi, Nefeli; Rubinos, Clio; Li, Leping et al. (2014) Connexin 46 (cx46) gap junctions provide a pathway for the delivery of glutathione to the lens nucleus. J Biol Chem 289:32694-702
Sellitto, Caterina; Li, Leping; Gao, Junyuan et al. (2013) AKT activation promotes PTEN hamartoma tumor syndrome-associated cataract development. J Clin Invest 123:5401-9

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