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1.
Epigenetics ; 12(1): 27-40, 2017 01 02.
Article in English | MEDLINE | ID: mdl-27824296

ABSTRACT

Despite the wealth of knowledge of transcription factors involved in lens development, little information exists about the role of DNA methylation in this process. Here, we investigated the role of DNA methylation in lens development and fiber cell differentiation using mice conditionally lacking maintenance or de novo methyltransferases in the lens lineage. We found that while Dnmt1 inactivation at the lens placode stage (via the Le-Cre transgene) led to lens DNA hypomethylation and severe lens epithelial apoptosis, lens fiber cell differentiation remained largely unaffected. The simultaneous deletion of phosphatase and tensin homolog (Pten) elevated the level of phosphorylated AKT and rescued many of the morphological defects and cell death in DNMT1-deficient lenses. With a different Cre driver (MLR10) we demonstrated that a small number of lens epithelial cells escaped Dnmt1-deletion and over-proliferated to compensate for the loss of Dnmt1-deleted cells, suggesting that lens epithelium possess a substantial capacity for self-renewal. Unlike lenses deficient for Dnmt1, inactivation of both Dnmt3a and Dnmt3b by either the Le-Cre or MLR10-Cre transgene did not result in any obvious lens phenotype prior to 10 months of age. Taken together, while lens epithelial cell survival requires DNMT1, morphologically normal lenses develop in the absence of both DNMT3A and DNMT3B.


Subject(s)
DNA (Cytosine-5-)-Methyltransferases/physiology , Lens, Crystalline/embryology , Organogenesis/genetics , Animals , Animals, Newborn , Cell Differentiation/genetics , DNA (Cytosine-5-)-Methyltransferase 1 , DNA (Cytosine-5-)-Methyltransferases/genetics , DNA Methylation/genetics , DNA Methyltransferase 3A , Embryo, Mammalian , Female , Gene Expression Regulation, Developmental , Gene Expression Regulation, Enzymologic , Lens, Crystalline/metabolism , Mice , Mice, Transgenic , Pregnancy , gamma-Crystallins/genetics , DNA Methyltransferase 3B
2.
Dev Biol ; 410(2): 150-163, 2016 Feb 15.
Article in English | MEDLINE | ID: mdl-26764128

ABSTRACT

Lens epithelial cells express many receptor tyrosine kinases (RTKs) that stimulate PI3K-AKT and RAS-RAF-MEK-ERK intracellular signaling pathways. These pathways ultimately activate the phosphorylation of key cellular transcription factors and other proteins that control proliferation, survival, metabolism, and differentiation in virtually all cells. Among RTKs in the lens, only stimulation of fibroblast growth factor receptors (FGFRs) elicits a lens epithelial cell to fiber cell differentiation response in mammals. Moreover, although the lens expresses three different Fgfr genes, the isolated removal of Fgfr2 at the lens placode stage inhibits both lens cell survival and fiber cell differentiation. Phosphatase and tensin homolog (PTEN), commonly known as a tumor suppressor, inhibits ERK and AKT activation and initiates both apoptotic pathways, and cell cycle arrest. Here, we show that the combined deletion of Fgfr2 and Pten rescues the cell death phenotype associated with Fgfr2 loss alone. Additionally, Pten removal increased AKT and ERK activation, above the levels of controls, in the presence or absence of Fgfr2. However, isolated deletion of Pten failed to stimulate ectopic fiber cell differentiation, and the combined deletion of Pten and Fgfr2 failed to restore differentiation-specific Aquaporin0 and DnaseIIß expression in the lens fiber cells.


Subject(s)
Cell Survival/physiology , PTEN Phosphohydrolase/metabolism , Receptor, Fibroblast Growth Factor, Type 2/metabolism , Signal Transduction , Animals , Cell Differentiation/physiology , Cell Proliferation/physiology , Lens, Crystalline/embryology , MAP Kinase Signaling System , Mice , PTEN Phosphohydrolase/genetics , PTEN Phosphohydrolase/physiology , Phosphorylation , Proto-Oncogene Proteins c-akt/metabolism , Proto-Oncogene Proteins c-jun/metabolism , Receptor, Fibroblast Growth Factor, Type 2/genetics , Receptor, Fibroblast Growth Factor, Type 2/physiology , Tumor Suppressor Protein p53/metabolism
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