Fibroblast growth factor receptor 2 (FGFR2) is required for corneal epithelial cell proliferation and differentiation during embryonic development.
Fibroblast growth factor receptor 2 (FGFR2) is required for corneal epithelial cell proliferation and differentiation during embryonic development.
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DOI：
10.1371/journal.pone.0117089
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发表时间：
2015
期刊：
影响因子：
3.7
通讯作者：
Reneker LW
中科院分区：
文献类型：
--
作者：
Zhang J;Upadhya D;Lu L;Reneker LW
成纤维细胞生长因子（FGF）在胚胎发育的许多方面发挥重要作用。在眼睛的发育过程中，透镜和角膜上皮细胞来自同一表面的外胚层组织。FGF受体（FGFR）信号传导对于透镜细胞分化和存活是必需的，但其在角膜发育中的作用尚未得到充分研究。在这项研究中，我们研究了Fgfr 2条件性基因敲除小鼠的角膜缺损，其中Cre表达在透镜诱导阶段由Pax 6 P0启动子激活。分析LeCre、Fgfr 2loxP/loxP小鼠（称为Fgfr 2CKO）的角膜以评估细胞增殖、分化和存活的变化。我们发现Fgfr 2CKO角膜的上皮层和基质层比WT角膜薄得多。在胚胎第12.5-13.5天（E12.5-13.5），在透镜囊泡从上覆表面外胚层脱离后不久，Fgfr 2CKO小鼠角膜上皮中的细胞增殖（通过Ki-67、BrdU和磷酸化组蛋白H3的标记指数判断）显著降低。在后期阶段，角膜上皮细胞分化标志物和下面的基质间充质细胞，角蛋白-12和keratocan，分别在Fgfr 2CKO角膜中不表达。此外，Pax 6，一种对眼睛发育至关重要的转录因子，在E16.5时不存在于Fgfr 2CKO突变体角膜上皮中，但在E12.5时正常表达，这表明FGFR 2信号传导是维持Pax 6在该组织中表达所必需的。有趣的是，FGFR 2在角膜上皮发育中的作用不依赖于ERK 1/2信号传导。与透镜相反，角膜中的细胞存活不需要FGFR 2。这项研究首次证明了FGFR 2在胚胎发育过程中通过ERK非依赖性途径控制细胞增殖和分化以及维持角膜上皮中Pax 6水平方面发挥重要作用。
Fibroblast growth factors (FGFs) play important roles in many aspects of embryonic development. During eye development, the lens and corneal epithelium are derived from the same surface ectodermal tissue. FGF receptor (FGFR)-signaling is essential for lens cell differentiation and survival, but its role in corneal development has not been fully investigated. In this study, we examined the corneal defects in Fgfr2 conditional knockout mice in which Cre expression is activated at lens induction stage by Pax6 P0 promoter. The cornea in LeCre, Fgfr2loxP/loxP mice (referred as Fgfr2CKO) was analyzed to assess changes in cell proliferation, differentiation and survival. We found that Fgfr2CKO cornea was much thinner in epithelial and stromal layer when compared to WT cornea. At embryonic day 12.5–13.5 (E12.5–13.5) shortly after the lens vesicle detaches from the overlying surface ectoderm, cell proliferation (judged by labeling indices of Ki-67, BrdU and phospho-histone H3) was significantly reduced in corneal epithelium in Fgfr2CKO mice. At later stage, cell differentiation markers for corneal epithelium and underlying stromal mesenchyme, keratin-12 and keratocan respectively, were not expressed in Fgfr2CKO cornea. Furthermore, Pax6, a transcription factor essential for eye development, was not present in the Fgfr2CKO mutant corneal epithelial at E16.5 but was expressed normally at E12.5, suggesting that FGFR2-signaling is required for maintaining Pax6 expression in this tissue. Interestingly, the role of FGFR2 in corneal epithelial development is independent of ERK1/2-signaling. In contrast to the lens, FGFR2 is not required for cell survival in cornea. This study demonstrates for the first time that FGFR2 plays an essential role in controlling cell proliferation and differentiation, and maintaining Pax6 levels in corneal epithelium via ERK-independent pathways during embryonic development.
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影响因子：
3.7
作者：
Dorà NJ;Collinson JM;Hill RE;West JD
通讯作者：
West JD
影响因子：
64.8
作者：
HILL, RE;FAVOR, J;VANHEYNINGEN, V
通讯作者：
VANHEYNINGEN, V
影响因子：
2.7
作者：
Collinson, JM;Quinn, JC;West, JD
通讯作者：
West, JD
影响因子：
--
作者：
Burgess D;Zhang Y;Siefker E;Vaca R;Kuracha MR;Reneker L;Overbeek PA;Govindarajan V
通讯作者：
Govindarajan V
影响因子：
10.5
作者：
Ashery-Padan, R;Marquardt, T;Gruss, P
通讯作者：
Gruss, P