Eye Hospital of China Medical University and the Department of Ophthalmology, the Fourth Affiliated Hospital of China Medical University, Provincial Key Laboratory of Lens Research, Liaoning, China.
Am J Pathol. 2012 Jun;180(6):2230-9. doi: 10.1016/j.ajpath.2012.02.017. Epub 2012 Apr 13.
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. MSX2 was recently implicated as a potential gene that is critical for anterior segment development. However, the role of MSX2 within the complex mechanisms of eye development remains elusive. Our present study observed the morphologic changes in conventional Msx2 knockout (KO) mice and found phenotypes consistent with Peters anomaly and microphthalmia seen in humans. The role of Msx2 in cornea and lens development was further investigated using IHC, in situ hybridization, and quantification of proliferative and apoptotic lens cells. Loss of Msx2 down-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 in Msx2 KO mice. The observed changes in the expression of FoxE3 suggest that Msx2 is 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 of MSX2 in Peters anomaly and the distinct function of MSX2 in regulating the growth and development of lens vesicles.
复杂的分子相互作用决定了导致成熟和功能正常的角膜和晶状体的发育步骤。彼得斯异常是前节发育不良的一种亚型，特别是由于角膜和晶状体的异常发育。MSX2 最近被认为是一个对前节发育至关重要的潜在基因。然而，MSX2 在眼睛发育的复杂机制中的作用仍然难以捉摸。本研究观察了常规 Msx2 敲除（KO）小鼠的形态变化，发现与人类所见的彼得斯异常和小眼球表型一致。我们使用免疫组织化学、原位杂交和增殖和凋亡晶状体细胞的定量分析进一步研究了 Msx2 在角膜和晶状体发育中的作用。Msx2 的缺失下调了 FoxE3 的表达，上调了晶状体中的 Prox1 和晶状体蛋白的表达。FoxE3 和 Prox1 的功能障碍以及早熟的 Prox1 和晶状体蛋白的表达导致晶状体小泡中的晶状体细胞周期紊乱，最终导致 Msx2 KO 小鼠的角膜 - 晶状体粘连和小眼球。FoxE3 表达的观察变化表明，Msx2 是控制早期眼睛发育关键靶基因转录的重要因素。这些结果提供了 MSX2 参与彼得斯异常的第一个直接遗传证据，以及 MSX2 在调节晶状体小泡生长和发育中的独特功能。
