Mutations in the human phosphatase and tensin homolog (PTEN) gene cause PTEN hamartoma tumor syndrome (PHTS), which includes cataract development among its diverse clinical pathologies. Currently, it is not known whether cataract formation in PHTS patients is secondary to other systemic problems, or the result of the loss of a critical function of PTEN within the lens. We generated a mouse line with a lens-specific deletion of Pten (PTEN KO) and identified a regulatory function for PTEN in lens ion transport. Specific loss of PTEN in the lens resulted in cataract. PTEN KO lenses exhibited a progressive age-related increase in intracellular hydrostatic pressure, along with, increased intracellular sodium concentrations, and reduced Na+/K+-ATPase activity. Collectively, these defects lead to lens swelling, opacities and ultimately organ rupture. Activation of AKT was highly elevated in PTEN KO lenses compared to WT mice. Additionally, pharmacological inhibition of AKT restored normal Na+/K+-ATPase activity in primary cultured lens cells and reduced lens pressure in intact lenses from PTEN KO animals. These findings identify a direct role for PTEN in the regulation of lens ion transport through an AKT-dependent modulation of Na+/K+-ATPase activity, and provide a new animal model to investigate cataract development in PHTS patients.
Caterina Sellitto, Leping Li, Junyuan Gao, Michael L. Robinson, Richard Z. Lin, Richard T. Mathias, Thomas W. White
(A) At P0, sagittal sections through the central region of WT lenses showed a normal appearance. (B) P0 PTEN KO lenses displayed small vacuoles in the equatorial cortex. (C and D) Coronal sections of P2 lenses confirmed the absence of vacuoles in WT animals (C), which were uniformly distributed across the equatorial region in PTEN KO mice (D). (E) Sagittal sections from P7 WT lenses showed normal differentiation of lens fibers from equatorial epithelial cells. (F) P7 PTEN KO lenses also showed normal fiber differentiation, in addition to numerous vacuoles immediately underneath the equatorial epithelium. Scale bars: 50 μm.