Transgenic overexpression of connexin50 induces cataracts

Chung, Joaquín; Berthoud, Viviana M.; Novak, L.A.; Zoltoski, Rebecca K.; Heilbrunn, B.; Minogue, Peter J.; Liu, Xiaoqin; Ebihara, Lisa; Kuszak, J.R.; Beyer, Eric C.

doi:10.1016/j.exer.2006.11.004

Cited by 27 publications

(24 citation statements)

References 51 publications

(73 reference statements)

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“…Therefore, it was somewhat surprising that the loss of N-cadherin did not have a significant effect on the ability of differentiating secondary lens fiber cells to form lateral adhesive interactions. While best-known for their role as lens channel/communication proteins, Connexin 50 (Cx50) and Aquaporin 0 (Aqp0) also can have cell adhesive function (Nielsen et al, 2001; Nielsen et al, 2003; Chung et al, 2007; Kumari and Varadaraj, 2009; Liu et al, 2011; Lo et al, 2014; Wang et al, 2016). Here, we investigated Cx50 and Aqp0, both molecules with fiber cell-specific patterns of expression in the lens, as potential mediators of lateral adhesive contacts between these cells in the N-cadcKO lens.…”

Section: Resultsmentioning

confidence: 99%

N-cadherin regulates signaling mechanisms required for lens fiber cell elongation and lens morphogenesis

Logan

Rajakaruna

Bowen

et al. 2017

Developmental Biology

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Tissue development and regeneration involve high-ordered morphogenetic processes that are governed by elements of the cytoskeleton in conjunction with cell adhesion molecules. Such processes are particularly important in the lens whose structure dictates its function. Studies of our lens-specific N-cadherin conditional knockout mouse (N-cadcKO) revealed an essential role for N-cadherin in the migration of the apical tips of differentiating lens fiber cells along the apical surfaces of the epithelium, a region termed the Epithelial Fiber Interface (EFI), that is necessary for normal fiber cell elongation and the morphogenesis. Studies of the N-cadcKO lens suggest that N-cadherin function in fiber cell morphogenesis is linked to the activation of Rac1 and myosin II, both signaling pathways central to the regulation of cell motility including determining the directionality of cellular movement. The absence of N-cadherin did not disrupt lateral contacts between fiber cells during development, and the maintenance of Aquaporin-0 and increased expression of EphA2 at cell-cell interfaces suggests that these molecules may function in this role. E-cadherin was maintained in newly differentiating fiber cells without interfering with expression of lens-specific differentiation proteins but was not able to replace N-cadherin function in these cells. The dependence of migration of the fiber cell apical domains along the EFI for lens morphogenesis on N-cadherin provides new insight into the process of tissue development.

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Section: Resultsmentioning

confidence: 99%

N-cadherin regulates signaling mechanisms required for lens fiber cell elongation and lens morphogenesis

Logan

Rajakaruna

Bowen

et al. 2017

Developmental Biology

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“…AQP0 belongs to the water transport family of integral channel proteins controling transport of water and some neutral solutes but not ions (Agre, 2004). Connexins, Cx46 and Cx50 (with Cx46 found mainly in the cortex and outer nuclear layers, and Cx50 found mainly in the nuclear core (Chung et al, 2007; Tenbroek et al, 1992; White et al, 1998)), form gap junctions between lens fiber cells and control the exchange of ions and small metabolites (glucose, amino acids) between lens cells (Mathias et al, 2010). Our results indicate that for human clear lenses the lipid bilayer portion of fiber cell membranes forms a highly hydrophobic barrier in both cortical and nuclear membranes for all investigated age groups (Fig.…”

Section: Discussionmentioning

confidence: 99%

Lipid domains in intact fiber-cell plasma membranes isolated from cortical and nuclear regions of human eye lenses of donors from different age groups

Raguž

Mainali

O’Brien

et al. 2015

Experimental Eye Research

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The results reported here clearly document changes in the properties and the organization of fiber-cell membrane lipids that occur with age, based on electron paramagnetic resonance (EPR) analysis of lens membranes of clear lenses from donors of age groups from 0 to 20, 21 to 40, and 61 to 80 years. The physical properties, including profiles of the alkyl chain order, fluidity, hydrophobicity, and oxygen transport parameter, were investigated using EPR spin-labeling methods, which also provide an opportunity to discriminate coexisting lipid domains and to evaluate the relative amounts of lipids in these domains. Fiber-cell membranes were found to contain three distinct lipid environments: bulk lipid domain, which appears minimally affected by membrane proteins, and two domains that appear due to the presence of membrane proteins, namely boundary and trapped lipid domains. In nuclear membranes the amount of boundary and trapped phospholipids as well as the amount of cholesterol in trapped lipid domains increased with the donors’ age and was greater than that in cortical membranes. The difference between the amounts of lipids in domains uniquely formed due to the presence of membrane proteins in nuclear and cortical membranes increased with the donors’ age. It was also shown that cholesterol was to a large degree excluded from trapped lipid domains in cortical membranes. It is evident that the rigidity of nuclear membranes was greater than that of cortical membranes for all age groups. The amount of lipids in domains of low oxygen permeability, mainly in trapped lipid domains, were greater in nuclear than cortical membranes and increased with the age of donors. These results indicate that the nuclear fiber cell plasma membranes were less permeable to oxygen than cortical membranes and become less permeable to oxygen with age. In clear lenses, age-related changes in the lens lipid and protein composition and organization appear to occur in ways that increase fiber cell plasma membrane resistance to oxygen permeation.

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“…The paper concludes that channel function not only depends on the sequence of connexin, but also on the gene locus it expresses, although the difference in the levels of connexin expression at different gene locus might be another possible factor attributing to this phenotype. Recently, transgenic mice overexpressing Cx50 driven by βB1-crystallin was reported [118]. Surprisingly, the lenses from these transgenic mice are smaller and developed cataracts even at postnatal day 1.…”

Section: Gap Junction and Hemichannels In Cataractogenesismentioning

confidence: 99%

Gap Junctions or Hemichannel-Dependent and Independent Roles of Connexins in Cataractogenesis and Lens Development

Jiang¹

2010

CMM

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In the last decade or so, increasing evidences suggest that the mutations of two connexin genes, GJA3 and GJA8, are directly linked to human congenital cataracts in North and Central America, Europe and Asia. GIA3 and GIA8 genes encode gap junction-forming proteins, connexin (Cx) 46 and Cx50, respectively. These two connexins are predominantly expressed in lens fiber cells. Majority of identified mutations are missense, and the mutated sites are scattered across various domains of connexin molecules. Genetic deletion of either of these two genes leads to the development of cataracts; however, the types of cataracts developed are distinctive. More interestingly, microphthalmia is only developed in Cx50, but not Cx46 deficient mice, suggesting the unique role of Cx50 in lens cell growth and development. Knockin studies with the replacement of Cx46 or Cx50 at their respective gene locus further demonstrate the unique properties of these two connexins. Furthermore, the function of Cx50 in epithelial-fiber differentiation appears to be independent of its conventional role in forming gap junction junction channels. Due to their specific functions in maintaining lens clarity and development, and their malfunctions resulting in lens cataractogenesis and developmental impairment, connexin molecules could be developed as potential drug targets for therapeutic intervention for treatment of cataracts and other eye disorders. Recent advances in basic research of lens connexins and the discoveries of clinical disorders as a result of lens connexin dysfunctions are summarized and discussed here.

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Transgenic overexpression of connexin50 induces cataracts

Cited by 27 publications

References 51 publications

N-cadherin regulates signaling mechanisms required for lens fiber cell elongation and lens morphogenesis

N-cadherin regulates signaling mechanisms required for lens fiber cell elongation and lens morphogenesis

Lipid domains in intact fiber-cell plasma membranes isolated from cortical and nuclear regions of human eye lenses of donors from different age groups

Gap Junctions or Hemichannel-Dependent and Independent Roles of Connexins in Cataractogenesis and Lens Development

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