An Epha4/Sipa1l3/Wnt pathway regulates eye development and lens maturation
An Epha4/Sipa1l3/Wnt pathway regulates eye development and lens maturation
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DOI：
10.1242/dev.147462
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发表时间：
2017-01-15
期刊：
影响因子：
4.6
通讯作者：
Kuehl, Susanne J.
中科院分区：
文献类型：
--
作者：
Rothe, Melanie;Kanwal, Noreen;Kuehl, Susanne J.
信号诱导增殖相关蛋白家族包含四个成员：SIPA1 和 SIPA1L1-3。人类 SIPA1L3 基因突变会导致先天性白内障。在非洲爪蟾中，Sipa1l3 功能的丧失会导致严重的眼睛表型，其特征是眼睛和晶状体较小，包括晶状体纤维细胞成熟缺陷。我们发现 Sipa1l3 和 Epha4 之间存在直接相互作用，为眼睛的正常发育构建了一个功能平台。 Epha4 缺陷表现出 Sipa1l3 的表型缺失，救援实验表明，Epha4 在眼睛发育过程中在 Sipa1l3 的上游发挥作用，而 Sipa1l3 和 Epha4 都是早期眼睛规范所必需的。 Epha4 或 Sipa1l3 缺失后的眼部表型部分由 rax 介导。我们证明，在正常眼睛发育过程中，Epha4 和 Sipa1l3 下游的经典 Wnt 信号传导受到抑制。 Sipa1l3 或 Epha4 的缺失会导致 axin2 表达上调，axin2 是 Wnt/β-catenin 的直接靶基因。与此相符，Sipa1l3 或 Epha4 的缺失可以通过阻断 Wnt/β-catenin 或激活非经典 Wnt 信号传导来挽救。因此，我们得出的结论是，这种病理机制会阻碍眼睛的正常发育和晶状体纤维细胞的成熟，从而导致先天性白内障。
The signal-induced proliferation-associated family of proteins comprises four members, SIPA1 and SIPA1L1-3. Mutations of the human SIPA1L3 gene result in congenital cataracts. In Xenopus, loss of Sipa1l3 function led to a severe eye phenotype that was distinguished by smaller eyes and lenses including lens fiber cell maturation defects. We found a direct interaction between Sipa1l3 and Epha4, building a functional platform for proper ocular development. Epha4 deficiency phenocopied loss of Sipa1l3 and rescue experiments demonstrated that Epha4 acts upstream of Sipa1l3 during eye development, with both Sipa1l3 and Epha4 required for early eye specification. The ocular phenotype, upon loss of either Epha4 or Sipa1l3, was partially mediated by rax. We demonstrate that canonical Wnt signaling is inhibited downstream of Epha4 and Sipa1l3 during normal eye development. Depletion of either Sipa1l3 or Epha4 resulted in an upregulation of axin2 expression, a direct Wnt/beta-catenin target gene. In line with this, Sipa1l3 or Epha4 depletion could be rescued by blocking Wnt/beta-catenin or activating non-canonical Wnt signaling. We therefore conclude that this pathomechanism prevents proper eye development and maturation of lens fiber cells, resulting in congenital cataracts.