Notch gain of function in mouse periocular mesenchyme downregulates FoxL2 and impairs eyelid levator muscle formation, leading to congenital blepharophimosis
Notch gain of function in mouse periocular mesenchyme downregulates FoxL2 and impairs eyelid levator muscle formation, leading to congenital blepharophimosis
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DOI：
10.1242/jcs.085001
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发表时间：
2011-08-01
影响因子：
4
通讯作者：
Liu, Chia-Yang
中科院分区：
文献类型：
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作者：
Zhang, Yujin;Kao, Winston W. -Y.;Liu, Chia-Yang
Notch信号对许多组织的形态发生和动态平衡起着关键作用。我们发现，小鼠眼球周围间充质细胞(POMCs)中Notch的异常激活，有助于角膜和眼皮基质的形成，导致眼球突出症。在POMC(N1-ICD)中过度表达Notch1胞内区(N1-ICD)的复合转基因小鼠对角膜的影响相对较小，但在眼睑形态发生过程中增加了细胞凋亡，抑制了细胞增殖。E15.5的眼皮闭合和出生时的眼皮形成不完整。在进一步的分析中，N1-ICD的过度表达通过下调转录因子FOXL2而损害了眼睑提肌肌的形成。这类似于FOXL2单倍体不足对人类的影响，后者会导致II型BPES(眼睑畸形、上睑下垂和内翻内翻综合征)。体外研究表明，低剂量的N1-ICD可增强FOXL2的表达，但高剂量可下调FOXL2的表达，这取决于Hes-1和Hey-1的激活程度。此外，CMV-FOXL2的转染增强了α-SMA启动子的活性。这些数据强烈表明，生理水平较低的Notch1对于POMCs中FOXL2的正确表达至关重要，而FOXL2又是Mueller肌肉形成和正常眼皮发育所必需的。
Notch signaling is pivotal for the morphogenesis and homeostasis of many tissues. We found that aberrant Notch activation in mouse neural-crest-derived periocular mesenchymal cells (POMCs), which contribute to the formation of corneal and eyelid stroma, results in blepharophimosis. Compound transgenic mice overexpressing the Notch1 intracellular domain (N1-ICD) in POMCs (POMC(N1-ICD)) showed relatively minor effects on the cornea, but increased cell apoptosis and decreased cell proliferation during eyelid morphogenesis. Eyelid closure at E15.5 and eyelid formation at birth were incomplete. In further analyses, overexpression of N1-ICD impaired eyelid levator smooth muscle formation by downregulating the transcription factor FoxL2. This is similar to the effect of haploinsufficiency of FOXL2 in humans, which results in type II BPES (blepharophimosis, ptosis and epicanthus inversus syndrome). In vitro studies showed that FoxL2 expression is augmented by a low dose of N1-ICD but was downregulated by a high dose, depending on the extent of Hes-1 and Hey-1 activation. Moreover, transfection of CMV-FoxL2 enhanced alpha-SMA promoter activity. These data strongly imply that a physiologically low level of Notch1 is crucial for proper FoxL2 expression in POMCs, which is, in turn, essential for Mueller muscle formation and normal eyelid development.