| First Author | Mao M | Year | 2022 |
| Journal | Matrix Biol | Volume | 110 |
| Pages | 151-173 | PubMed ID | 35525525 |
| Mgi Jnum | J:325161 | Mgi Id | MGI:7283851 |
| Doi | 10.1016/j.matbio.2022.05.001 | Citation | Mao M, et al. (2022) Elevated TGFbeta signaling contributes to ocular anterior segment dysgenesis in Col4a1 mutant mice. Matrix Biol |
| abstractText | Ocular anterior segment dysgenesis (ASD) refers to a collection of developmental disorders affecting the anterior structures of the eye. Although a number of genes have been implicated in the etiology of ASD, the underlying pathogenetic mechanisms remain unclear. Mutations in genes encoding collagen type IV alpha 1 (COL4A1) and alpha 2 (COL4A2) cause Gould syndrome, a multi-system disorder that often includes ocular manifestations such as ASD and glaucoma. COL4A1 and COL4A2 are abundant basement membrane proteins that provide structural support to tissues and modulate signaling through interactions with other extracellular matrix proteins, growth factors, and cell surface receptors. In this study, we used a combination of histological, molecular, genetic and pharmacological approaches to demonstrate that altered TGFbeta signaling contributes to ASD in mouse models of Gould syndrome. We show that TGFbeta signaling was elevated in anterior segments from Col4a1 mutant mice and that genetically reducing TGFbeta signaling partially prevented ASD. Notably, we identified distinct roles for TGFbeta1 and TGFbeta2 in ocular defects observed in Col4a1 mutant mice. Importantly, we show that pharmacologically promoting type IV collagen secretion or reducing TGFbeta signaling ameliorated ocular pathology in Col4a1 mutant mice. Overall, our findings demonstrate that altered TGFbeta signaling contributes to COL4A1-related ocular dysgenesis and implicate this pathway as a potential therapeutic target for the treatment of Gould syndrome. |
