Pax6 dosage requirements in iris and ciliary body differentiation
Pax6 dosage requirements in iris and ciliary body differentiation
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DOI：
10.1016/j.ydbio.2009.06.023
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发表时间：
2009-09-01
影响因子：
2.7
通讯作者：
Ashery-Padan, Ruth
中科院分区：
文献类型：
--
作者：
Davis, Noa;Yoffe, Chen;Ashery-Padan, Ruth
Pax6是一种高度保守的转录因子，控制着多种器官的形态发生。Pax6剂量的变化已被证明会影响多种组织的形成。PAX6单倍不全导致无虹膜，一种以虹膜发育不全为主要特征的泛眼疾病。在这里，我们采用了一个模块化的系统，其中包括Pax6的空和过表达的条件等位基因。使用活跃于虹膜和睫状体（CB）原基的Tyrp2-Cre系，使我们能够研究不同剂量的Pax6对这些眼部亚器官发育的影响。我们的研究结果表明，这些区域缺乏Pax6会导致虹膜和CB发育不良，而杂合性会阻碍虹膜的生长和虹膜括约肌的成熟。Pax6典型剪接变体的过表达，而非选择性剪接变体的过表达，会导致虹膜括约肌的严重结构畸变和增生。一项剪接变体特异性修复实验显示，两种剪接变体都能纠正虹膜发育不全，而只有典型剪接变体能修复括约肌。总的来说，这些发现表明Pax6在cbb和虹膜形成中的剂量敏感作用。(C) 2009爱思唯尔公司版权所有。
Pax6 is a highly conserved transcription factor that controls the morphogenesis of various organs. Changes in Pax6 dosage have been shown to affect the formation of multiple tissues. PAX6 haploinsufficiency leads to aniridia, a pan-ocular disease primarily characterized by iris hypoplasia. Herein, we employ a modular system that includes null and overexpressed conditional alleles of Pax6. The use of the Tyrp2-Cre line, active in iris and ciliary body (CB) primordium, enabled us to investigate the effect of varying dosages of Pax6 on the development of these ocular sub-organs. Our findings show that a lack of Pax6 in these regions leads to dysgenesis of the iris and CB, while heterozygosity impedes growth of the iris and maturation of the iris sphincter. Overexpression of the canonical, but not the alternative splice variant of Pax6 results in severe structural aberrations of the CB and hyperplasia of the iris sphincter. A splice variant-specific rescue experiment revealed that both splice variants are able to correct iris hypoplasia, while only the canonical form rescues the sphincter. Overall, these findings demonstrate the dosage-sensitive roles of Pax6 in the formation of both the CB and the iris. (C) 2009 Elsevier Inc. All rights reserved.