Discipline of Anatomy and Histology, Bosch Institute, The University of Sydney, NSW, Australia.
Discipline of Anatomy and Histology, Bosch Institute, The University of Sydney, NSW, Australia; Save Sight Institute, The University of Sydney, NSW, Australia.
Exp Eye Res. 2019 Jan;178:160-175. doi: 10.1016/j.exer.2018.09.019. Epub 2018 Oct 2.
Spred, like Sprouty (Spry) and also Sef proteins, have been identified as important regulators of receptor tyrosine kinase (RTK)-mediated MAPK/ERK-signaling in various developmental systems, controlling cellular processes such as proliferation, migration and differentiation. Spreds are widely expressed during early embryogenesis, and in the eye lens, become more localised in the lens epithelium with later development, overlapping with other antagonists including Spry. Given the synexpression of Spreds and Spry in lens, in order to gain a better understanding of their specific roles in regulating growth factor mediated-signaling and cell behavior, we established and characterised lines of transgenic mice overexpressing Spred1 or Spred2, specifically in the lens. This overexpression of Spreds resulted in a small lens phenotype during ocular morphogenesis, retarding its growth by compromising epithelial cell proliferation and fiber differentiation. These in situ findings were shown to be dependent on the ability of Spreds to suppress MAPK-signaling, in particular FGF-induced ERK1/2-signaling in lens cells. This was validated in vitro using lens epithelial explants, that highlighted the overlapping role of Spreds with Spry2, but not Spry1. This study provides insights into the putative function of Spreds and Spry in situ, some overlapping and some distinct, and their importance in regulating lens cell proliferation and fiber differentiation contributing to lens and eye growth.
Spred 蛋白与 Sprouty（Spry）和 Sef 蛋白一样，被鉴定为受体酪氨酸激酶（RTK）-介导的 MAPK/ERK 信号通路在各种发育系统中的重要调节因子，控制细胞过程，如增殖、迁移和分化。Spred 在胚胎早期广泛表达，在晶状体中，随着后期发育变得更加局限于晶状体上皮，与包括 Spry 在内的其他拮抗剂重叠。鉴于 Spred 和 Spry 在晶状体中的共表达，为了更好地理解它们在调节生长因子介导的信号和细胞行为中的特定作用，我们建立并表征了特异性在晶状体中过表达 Spred1 或 Spred2 的转基因小鼠系。Spreds 的过表达导致眼球形态发生过程中的小眼表型，通过损害上皮细胞增殖和纤维分化来阻碍晶状体的生长。这些原位发现依赖于 Spreds 抑制 MAPK 信号的能力，特别是在晶状体细胞中抑制 FGF 诱导的 ERK1/2 信号。这在体外使用晶状体上皮外植体得到了验证，突出了 Spreds 与 Spry2 的重叠作用，但与 Spry1 没有重叠。这项研究提供了关于 Spreds 和 Spry 在原位的可能功能的见解，有些重叠，有些不同，它们在调节晶状体细胞增殖和纤维分化中对晶状体和眼睛生长的重要性。
