PDF(Pubmed)
Abstract：
The development and growth of the eye depends on normal lens morphogenesis and its growth. This growth, in turn, is dependent on coordinated proliferation of the lens epithelial cells and their subsequent differentiation into fiber cells. These cellular processes are tightly regulated to maintain the precise cellular structure and size of the lens, critical for its transparency and refractive properties. Growth factor-mediated MAPK signaling driven by ERK1/2 has been reported as essential for regulating cellular processes of the lens, with ERK1/2 signaling tightly regulated by endogenous antagonists, including members of the Sprouty and related Spred families. Our previous studies have demonstrated the importance of both these inhibitory molecules in lens and eye development. In this study, we build on these findings to highlight the importance of Spreds in regulating early lens morphogenesis by modulating ERK1/2-mediated lens epithelial cell proliferation and fiber differentiation. Conditional loss of both Spred1 and Spred2 in early lens morphogenesis results in elevated ERK1/2 phosphorylation, hyperproliferation of lens epithelia, and an associated increase in the rate of fiber differentiation. This results in transient microphakia and microphthalmia, which disappears, owing potentially to compensatory Sprouty expression. Our data support an important temporal role for Spreds in the early stages of lens morphogenesis and highlight how negative regulation of ERK1/2 signaling is critical for maintaining lens proliferation and fiber differentiation in situ throughout life.
摘要：
眼睛的发育和生长取决于正常的晶状体形态发生及其生长。这种增长,反过来,依赖于晶状体上皮细胞的协调增殖及其随后分化成成纤维细胞。这些细胞过程受到严格的调节，以保持晶状体的精确细胞结构和大小，对其透明度和折射性能至关重要。据报道，由ERK1/2驱动的生长因子介导的MAPK信号传导对于调节晶状体的细胞过程至关重要，ERK1/2信号受到内源性拮抗剂的严格调节，包括Sprouty和相关的Spred家族的成员。我们先前的研究已经证明了这两种抑制分子在晶状体和眼睛发育中的重要性。在这项研究中,我们在这些发现的基础上强调了Spreds通过调节ERK1/2介导的晶状体上皮细胞增殖和纤维分化来调节早期晶状体形态发生的重要性。早期晶状体形态发生中Spred1和Spred2的条件丢失导致ERK1/2磷酸化升高,晶状体上皮过度增生,以及纤维分化率的相关增加。这导致了短暂的microphakia和小眼症，它消失了，由于潜在的补偿性发芽表达。我们的数据支持Spreds在晶状体形态发生的早期阶段的重要时间作用，并强调ERK1/2信号的负调节对于维持晶状体增殖和纤维分化至关重要。
