Loss of Msx2 function down-regulates the FoxE3 expression and results in anterior segment dysgenesis resembling Peters anomaly.
Loss of Msx2 function down-regulates the FoxE3 expression and results in anterior segment dysgenesis resembling Peters anomaly.
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DOI：
10.1016/j.ajpath.2012.02.017
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发表时间：
2012-06
期刊：
影响因子：
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通讯作者：
Jiangyue Zhao;K. Kawai;Hongyan Wang;Di Wu;Mingwu Wang;Zhicao Yue;Jinsong Zhang;Yi-hsin Liu
中科院分区：
文献类型：
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作者：
Jiangyue Zhao;K. Kawai;Hongyan Wang;Di Wu;Mingwu Wang;Zhicao Yue;Jinsong Zhang;Yi-hsin Liu
复杂的分子相互作用决定了导致成熟和功能性角膜和透镜的发育步骤。Peters异常是眼前节发育不全的一种亚型，尤其是由于角膜和晶状体的发育异常，MSX 2被认为是眼前节发育的关键基因。然而，MSX 2在眼睛发育的复杂机制中的作用仍然难以捉摸。本研究观察了Msx 2基因敲除（KO）小鼠的形态学变化，发现了与人类Peters异常和小眼症一致的表型。Msx 2在角膜和透镜发育中的作用通过免疫组化、原位杂交和定量增殖和凋亡的透镜细胞进一步研究。Msx 2的缺失下调了透镜中FoxE 3的表达，上调了Prox 1和晶状体蛋白的表达。FoxE 3和Prox 1功能障碍以及Prox 1和晶状体蛋白的早熟表达导致透镜囊泡中透镜细胞周期紊乱，并最终导致Msx 2 KO小鼠的角膜-晶状体样粘连和小眼球。观察到的FoxE 3表达变化表明Msx 2是控制对早期眼睛发育至关重要的靶基因转录的重要贡献者。这些结果为MSX 2参与Peters异常和MSX 2调节透镜囊泡生长发育提供了第一个直接的遗传学证据。
Complex molecular interactions dictate the developmental steps that lead to a mature and functional cornea and lens. Peters anomaly is one subtype of anterior segment dysgenesis especially due to abnormal development of the cornea and lens.MSX2was recently implicated as a potential gene that is critical for anterior segment development. However, the role ofMSX2within the complex mechanisms of eye development remains elusive. Our present study observed the morphologic changes in conventionalMsx2knockout (KO) mice and found phenotypes consistent with Peters anomaly and microphthalmia seen in humans. The role ofMsx2in cornea and lens development was further investigated using IHC, in situ hybridization, and quantification of proliferative and apoptotic lens cells. Loss ofMsx2down-regulated FoxE3 expression and up-regulated Prox1 and crystallin expression in the lens. The FoxE3 and Prox1 malfunction and precocious Prox1 and crystallin expression contribute to a disturbed lens cell cycle in lens vesicles and eventually to cornea-lentoid adhesions and microphthalmia inMsx2KO mice. The observed changes in the expression of FoxE3 suggest thatMsx2is an important contributor in controlling transcription of target genes critical for early eye development. These results provide the first direct genetic evidence of the involvement ofMSX2in Peters anomaly and the distinct function ofMSX2in regulating the growth and development of lens vesicles.