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Thomas W. White, Caterina Sellitto, Leping Li, Hong-Zhan Wang, Michael L. Robinson, Miduturu Srinivas, Richard Z. Lin; Interactions Between Gap Junctional Communication And Phosphoinositide 3-kinase Signaling In Lens Growth. Invest. Ophthalmol. Vis. Sci. 2011;52(14):3928.
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© ARVO (1962-2015); The Authors (2016-present)
Both connexin mediated coupling and signal transduction pathways have been shown to play critical roles in lens growth and development, but little is known about possible interactions between these two intercellular communication systems. We have previously identified an interaction between mitogen activated protein kinase (MAPK) signaling and junctional communication mediated by connexin50 (Cx50), suggesting that gap junctional communication and signal transduction pathways may work together during postnatal lens development. To further investigate how coupling and signal transduction pathways interact to regulate lens growth, we have generated and examined mice where components of the phosphoinositide 3-kinase (PI3K) signaling pathway were conditionally deleted in the mouse lens and examined interactions between PI3K signaling and Cx50.
p110alphaflox/flox mice were interbred with MLR10 Cre mice in order to obtain p110alphaflox/flox-MLR10 Cre animals. Lenses of age-matched animals were dissected, photographed, and lens volumes were calculated from the measured diameters. Cx50 coupling in vivo was measured in dispersed primary cells from transgenic lenses using dual whole cell patch clamp. Cx50 coupling in vitro was measured in transfected HeLa cells in the presence or absence of inhibitors of PI3K and Akt. Deletion of PI3K, and levels of phosphorylated and total Akt were determined by western blotting. Mitotic activity was detected by immunofluorescent staining of phospho-histone3.
Lens specific knockout of p110alpha resulted in a statistically significant reduction of lens size by >30% at 1 week of age that persisted throughout life. This reduction in lens size was correlated with a statistically significant reduction in postnatal lens mitosis and a large reduction in levels of Akt activation. Pharmacological inhibition of either p110alpha, or Akt, significantly inhibited Cx50 mediated intercellular communication in vitro. In addition, Cx50 coupling was greatly reduced in vivo using primary cultured cells from p110alpha knockout lenses.
These data suggest that the PI3K signaling pathway, like Cx50 mediated junctional communication, plays an important role in the regulation of lens size. They further suggest that PI3K signaling and Cx50 may interact in the regulation of postnatal lens growth.
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