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.

眼前节发育不全（ASD）是指影响眼睛前部结构的一系列发育障碍。尽管许多基因与 ASD 的病因有关，但潜在的发病机制仍不清楚。编码 IV 型胶原蛋白 α 1 (COL4A1) 和 α 2 (COL4A2) 的基因突变会导致古尔德综合征，这是一种多系统疾病，通常包括自闭症谱系障碍 (ASD) 和青光眼等眼部症状。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、生长因子和细胞表面受体的相互作用调节信号传导。在这项研究中，我们结合了组织学、分子、遗传学和药理学方法来证明 TGFβ 信号传导的改变有助于古尔德综合征小鼠模型中的自闭症谱系障碍 (ASD)。我们发现Col4a1突变小鼠的眼前节中 TGFβ 信号传导升高，并且通过基因方法减少 TGFβ 信号传导可以部分预防 ASD。值得注意的是，我们确定了 TGFβ1 和 TGFβ2 在Col4a1突变小鼠眼部缺陷中的不同作用。重要的是，我们发现，通过药理学促进 IV 型胶原分泌或减少 TGFβ 信号传导可改善Col4a1突变小鼠的眼部病理学。总体而言，我们的研究结果表明，TGFβ 信号传导的改变会导致 COL4A1 相关的眼部发育不全，并表明该通路是治疗古尔德综合征的潜在治疗靶点。