Department of Physiology & Biophysics, Stony Brook University School of Medicine, Stony Brook, NY 11794, USA.
Cells. 2022 Aug 30;11(17):2708. doi: 10.3390/cells11172708.
We have previously shown that the conditional deletion of either the p110α catalytic subunit of phosphatidylinositol 3-kinase (PI3K), or its opposing phosphatase, phosphatase and tensin homolog (PTEN), had distinct effects on lens growth and homeostasis. The deletion of p110α reduced the levels of phosphorylated Akt and equatorial epithelial cell proliferation, and resulted in smaller transparent lenses in adult mice. The deletion of PTEN increased levels of phosphorylated Akt, altered lens sodium transport, and caused lens rupture and cataract. Here, we have generated conditional p110α/PTEN double-knockout mice, and evaluated epithelial cell proliferation and lens homeostasis. The double deletion of p110α and PTEN rescued the defect in lens size seen after the single knockout of p110α, but accelerated the lens rupture phenotype seen in PTEN single-knockout mice. Levels of phosphorylated Akt in double-knockout lenses were significantly higher than in wild-type lenses, but not as elevated as those reported for PTEN single-knockout lenses. These results showed that the double deletion of the p110α catalytic subunit of PI3K and its opposing phosphatase, PTEN, exacerbated the rupture defect seen in the single PTEN knockout and alleviated the growth defect observed in the single p110α knockout. Thus, the integrity of the PI3K signaling pathway was absolutely essential for proper lens homeostasis, but not for lens growth.
我们之前已经表明，磷脂酰肌醇 3-激酶（PI3K）的 p110α 催化亚单位或其拮抗磷酸酶磷酸酶和张力蛋白同源物（PTEN）的条件缺失对晶状体生长和内稳态有不同的影响。p110α 的缺失降低了磷酸化 Akt 的水平和赤道上皮细胞的增殖，导致成年小鼠的透明晶状体变小。PTEN 的缺失增加了磷酸化 Akt 的水平，改变了晶状体的钠转运，并导致晶状体破裂和白内障。在这里，我们生成了条件性 p110α/PTEN 双敲除小鼠，并评估了上皮细胞增殖和晶状体内稳态。p110α 和 PTEN 的双缺失挽救了 p110α 单敲除后晶状体大小的缺陷，但加速了 PTEN 单敲除小鼠中晶状体破裂的表型。双敲除晶状体中磷酸化 Akt 的水平明显高于野生型晶状体，但不如 PTEN 单敲除晶状体中报道的水平高。这些结果表明，PI3K 信号通路的 p110α 催化亚单位和其拮抗磷酸酶 PTEN 的双缺失加剧了单敲除 PTEN 中观察到的破裂缺陷，并减轻了单敲除 p110α 中观察到的生长缺陷。因此，PI3K 信号通路的完整性对于适当的晶状体内稳态绝对必要，但对于晶状体生长则不是必需的。
