Lens induction requires attenuation of ERK signaling by Nf1
Lens induction requires attenuation of ERK signaling by Nf1
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DOI：
10.1093/hmg/ddr014
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发表时间：
2011-04-01
影响因子：
3.5
通讯作者：
Zhang, Xin
中科院分区：
文献类型：
--
作者：
Carbe, Christian;Zhang, Xin
无晶状体是一种罕见的人类先天性疾病，其遗传病因在很大程度上尚不清楚。即使在模式生物中，也很少有突变会导致如此严重的眼部缺陷。在这项研究中，我们发现人类1型神经纤维瘤病综合征的Ras GTPase基因Nf1的纯合缺失导致小鼠晶状体发育不良。尽管Nf1突变体的早期晶状体发育正常，但晶状体诱导因细胞增殖不足而中断。进一步分析表明，细胞外信号调节激酶（ERK）信号最初在内翻晶状体基板中升高，但在晶状体囊泡期，ERK磷酸化显著降低。只有在腹腔注射ERK磷酸化抑制剂U0126后，Nf1突变体的晶状体发育才得以恢复。已知ras -丝裂原活化蛋白激酶（MAPK）信号过度活跃可导致人类神经-心-面-皮肤（NCFC）综合征。作为nfc家族基因的一员，Nf1首次证明了Ras-MAPK激酶信号通路的衰减对晶状体的正常发育至关重要。
Aphakia (lack of lens) is a rare human congenital disorder with its genetic etiology largely unknown. Even in model organisms, very few mutations are known to result in such a drastic ocular defect. In this study, we have shown that homozygous deletion of Nf1, the Ras GTPase gene underlying human neurofibromatosis type 1 syndrome, causes lens dysgenesis in mouse. Although early lens specification proceeded normally in Nf1 mutants, lens induction was disrupted due to deficient cell proliferation. Further analysis showed that extracellular signal-regulated kinase (ERK) signaling was initially elevated in the invaginating lens placode, but by the lens vesicle stage, ERK phosphorylation was significantly reduced. Only after intraperitoneal treatment of U0126, an inhibitor of ERK phosphorylation, was lens development restored in Nf1 mutants. Hyperactive Ras-mitogen-activated protein kinase (MAPK) signaling is known to cause neuro-cardiofacial-cutaneous (NCFC) syndromes in humans. As a member of NCFC family genes, Nf1 represents the first example that attenuation of Ras-MAPK kinase signaling pathway is essential for normal lens development.