PDF(Pubmed)
Abstract：
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 TGFβ signaling contributes to ASD in mouse models of Gould syndrome. We show that TGFβ signaling was elevated in anterior segments from Col4a1 mutant mice and that genetically reducing TGFβ signaling partially prevented ASD. Notably, we identified distinct roles for TGFβ1 and TGFβ2 in ocular defects observed in Col4a1 mutant mice. Importantly, we show that pharmacologically promoting type IV collagen secretion or reducing TGFβ signaling ameliorated ocular pathology in Col4a1 mutant mice. Overall, our findings demonstrate that altered TGFβ signaling contributes to COL4A1-related ocular dysgenesis and implicate this pathway as a potential therapeutic target for the treatment of Gould syndrome.
摘要：
眼前节发育不全(ASD)是指影响眼睛前部结构的发育障碍的集合。尽管许多基因与ASD的病因有关，潜在的致病机制仍不清楚.编码IV型胶原α1（COL4A1）和α2（COL4A2）的基因突变引起古尔德综合征，多系统疾病，通常包括眼部表现，如ASD和青光眼。COL4A1和COL4A2是丰富的基底膜蛋白，为组织提供结构支持，并通过与其他细胞外基质蛋白的相互作用来调节信号传导。生长因子，和细胞表面受体。在这项研究中,我们使用了组织学的组合，分子，遗传和药理学方法证明TGFβ信号传导改变有助于Gould综合征小鼠模型中的ASD。我们表明，TGFβ信号在Col4a1突变小鼠的前段升高，并且遗传减少TGFβ信号部分阻止了ASD。值得注意的是,我们确定了TGFβ1和TGFβ2在Col4a1突变小鼠眼部缺损中的不同作用.重要的是,我们表明，在Col4a1突变小鼠中，药理学上促进IV型胶原蛋白分泌或减少TGFβ信号传导可以改善眼部病理。总的来说,我们的研究结果表明,TGFβ信号传导的改变有助于COL4A1相关的眼部发育不全,并暗示该通路是治疗Gould综合征的潜在治疗靶点.
