Regulation of ocular lens development by Smad-interacting protein 1 involving Foxe3 activation
Regulation of ocular lens development by Smad-interacting protein 1 involving Foxe3 activation
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DOI：
10.1242/dev.02022
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发表时间：
2005-10-01
期刊：
影响因子：
4.6
通讯作者：
Kondoh, H
中科院分区：
文献类型：
--
作者：
Yoshimoto, A;Saigou, Y;Kondoh, H
SIP1是一种与Smad结合的锌指同源域转录因子，在胚胎发育中具有重要的功能，但其在单个组织中的作用及其与Smad蛋白相互作用的意义尚未完全确定。在晶状体谱系中，SIP1的表达在晶状体胎盘诱导后被激活，随着晶状体的发育，SIP1的表达定位于晶状体上皮细胞和未成熟晶状体纤维所在的弓形区域。使用携带晶状体特异性Cre重组酶基因的纯合SIP1的小鼠进行晶状体谱系特异性SIP1基因的灭活。这导致了一个连接到表面外胚层的小的中空晶状体的发育，识别了晶状体发育中依赖SIP1的两个步骤。晶状体柄的持久性类似于Foxe3突变小鼠的缺陷，SIP1缺陷晶状体失去Foxe3表达，将Foxe3置于SIP1下游。在SIP1缺陷的晶状体中，产生了表达β晶状体蛋白的未成熟纤维细胞，但没有表达γ晶状体蛋白的成熟纤维细胞，这表明晶状体纤维成熟需要SIP1的活性。6.2kb的Foxe3启动子区域控制LacZ转基因在发育中的晶状体中的表达，在-1.26kb的上游发现了晶状体的主要和次要元件。通过转染实验，Foxe3启动子被SIP1激活，Smad8以依赖于SIP1的Smad结合结构域的方式进一步增强这种激活。这种SIP1依赖的激活和Smad8的增强是通过1.26kb的近端启动子发生的，并且与晶状体特异性调控是分开的。这是首次证明Smad相互作用在调节SIP1活性中的重要性。
Sip1, a Smad-binding zinc-finger homeodomain transcription factor, has essential functions in embryonic development, but its role in individual tissues and the significance of its interaction with Smad proteins have not been fully characterized. In the lens lineage, Sip1 expression is activated after lens placode induction, and as the lens develops, the expression is localized in the lens epithelium and bow region where immature lens fibers reside. The lens-lineage-specific inactivation of the Sip1 gene was performed using mice homozygous for floxed Sip1 that carry a lens-specific Cre recombinase gene. This caused the development of a small hollow lens connected to the surface ectoderm, identifying two Sip1-dependent steps in lens development. The persistence of the lens stalk resembles a defect in Foxe3 mutant mice, and Sip1 defective lenses lose Foxe3 expression, placing Foxe3 downstream of Sip1. In the Sip1-defective lens, beta-crystallin- expressing immature lens fiber cells were produced, but gamma-crystallin-expressing mature fiber cells were absent, indicating the requirement for Sip1 activity in lens fiber maturation. A 6.2 kb Foxe3 promoter region controlled lacZ transgene expression in the developing lens, where major and minor lens elements were identified upstream of -1.26 kb. Using transfection assays, the Foxe3 promoter was activated by Sip1 and this activation is further augmented by Smad8 in the manner dependent on the Smad-binding domain of Sip1. This Sip1-dependent activation and its augmentation by Smad8 occur using the proximal 1.26 kb promoter, and are separate from lens-specific regulation. This is the first demonstration of the significance of Smad interaction in modulating Sip1 activity.