?1-Integrin Deletion From the Lens Activates Cellular Stress Responses Leading to Apoptosis and Fibrosis.

ABSTRACT: Previous research showed that the absence of ?1-integrin from the mouse lens after embryonic day (E) 13.5 (?1MLR10) leads to the perinatal apoptosis of lens epithelial cells (LECs) resulting in severe microphthalmia. This study focuses on elucidating the molecular connections between ?1-integrin deletion and this phenotype.RNA sequencing was performed to identify differentially regulated genes (DRGs) in ?1MLR10 lenses at E15.5. By using bioinformatics analysis and literature searching, Egr1 (early growth response 1) was selected for further study. The activation status of certain signaling pathways (focal adhesion kinase [FAK]/Erk, TGF-?, and Akt signaling) was studied via Western blot and immunohistochemistry. Mice lacking both ?1-integrin and Egr1 genes from the lenses were created (?1MLR10/Egr1-/-) to study their relationship.RNA sequencing identified 120 DRGs that include candidates involved in the cellular stress response, fibrosis, and/or apoptosis. Egr1 was investigated in detail, as it mediates cellular stress responses in various cell types, and is recognized as an upstream regulator of numerous other ?1MLR10 lens DRGs. In ?1MLR10 mice, Egr1 levels are elevated shortly after ?1-integrin loss from the lens. Further, pErk1/2 and pAkt are elevated in ?1MLR10 LECs, thus providing the potential signaling mechanism that causes Egr1 upregulation in the mutant. Indeed, deletion of Egr1 from ?1MLR10 lenses partially rescues the microphthalmia phenotype.?1-integrin regulates the appropriate levels of Erk1/2 and Akt phosphorylation in LECs, whereas its deficiency results in the overexpression of Egr1, culminating in reduced cell survival. These findings provide insight into the molecular mechanism underlying the microphthalmia observed in ?1MLR10 mice.

SUBMITTER: Wang Y 

PROVIDER: S-EPMC5539801 | biostudies-literature | 2017 Aug

REPOSITORIES: biostudies-literature