Liu Hong, Xu Shunbin, Wang Yaping, Mazerolle Chantal, Thurig Sherry, Coles Brenda L K, Ren Jian-Ching, Taketo Makoto Mark, van der Kooy Derek, Wallace Valerie A
Molecular Medicine Program, Ottawa Health Research Institute, 501 Smyth Road, Ottawa, Ontario, Canada K1H 8L6.
Dev Biol. 2007 Aug 1;308(1):54-67. doi: 10.1016/j.ydbio.2007.04.052. Epub 2007 May 16.
The epithelial layers of the ciliary body (CB) and iris are non-neural structures that differentiate from the anterior region of the eyecup, the ciliary margin (CM). We show here that activation of the canonical Wnt signaling pathway is sufficient and necessary for the normal development of anterior eye structures. Pharmacological activation of beta-catenin signaling with lithium (Li(+)) treatment in retinal explants in vitro induced the ectopic expression of the CM markers Otx1 and Msx1. Cre-mediated stabilization of beta-catenin expression in the peripheral retina in vivo induced a cell autonomous upregulation of CM markers at the expense of neural retina (NR) markers and inhibited neurogenesis. Consistent with a cell autonomous conversion to peripheral eye fates, the proliferation index in the region of the retina that expressed stabilized beta-catenin was identical to the wild-type CM and there was an expansion of CB-like structures at later stages. Conversely, Cre-mediated inactivation of beta-catenin reduced CM marker expression as well as the size of the CM and CB/iris. Aberrant CB development in both mouse models was also associated with a reduction in the number of retinal stem cells in vitro. In summary, activation of canonical Wnt signaling is sufficient to promote the development of peripheral eyecup fates at the expense of the NR and is also required for the normal development of anterior eyecup structures.
睫状体（CB）和虹膜的上皮层是非神经结构，它们从眼杯的前部区域即睫状缘（CM）分化而来。我们在此表明，经典Wnt信号通路的激活对于眼前部结构的正常发育是充分且必要的。体外在视网膜外植体中用锂（Li⁺）处理进行β-连环蛋白信号的药理学激活，诱导了CM标志物Otx1和Msx1的异位表达。体内通过Cre介导的外周视网膜中β-连环蛋白表达的稳定化，以神经视网膜（NR）标志物为代价诱导了CM标志物的细胞自主上调，并抑制了神经发生。与向周边眼命运的细胞自主转变一致，表达稳定化β-连环蛋白的视网膜区域的增殖指数与野生型CM相同，并且在后期阶段出现了类似CB的结构扩张。相反，Cre介导的β-连环蛋白失活降低了CM标志物的表达以及CM和CB/虹膜的大小。两种小鼠模型中异常的CB发育也与体外视网膜干细胞数量的减少有关。总之，经典Wnt信号的激活足以促进以NR为代价的周边眼杯命运的发育，并且也是眼前部眼杯结构正常发育所必需的。
