Hägglund Anna-Carin, Jones Iwan, Carlsson Leif
Umeå Center for Molecular Medicine (UCMM), Umeå University, Umeå 901 87, Sweden.
Umeå Center for Molecular Medicine (UCMM), Umeå University, Umeå 901 87, Sweden
Dis Model Mech. 2017 Mar 1;10(3):245-257. doi: 10.1242/dmm.028605.
Development of the cornea, lens, ciliary body and iris within the anterior segment of the eye involves coordinated interaction between cells originating from the ciliary margin of the optic cup, the overlying periocular mesenchyme and the lens epithelium. Anterior segment dysgenesis (ASD) encompasses a spectrum of developmental syndromes that affect these anterior segment tissues. ASD conditions arise as a result of dominantly inherited genetic mutations and result in both ocular-specific and systemic forms of dysgenesis that are best exemplified by aniridia and Axenfeld-Rieger syndrome, respectively. Extensive clinical overlap in disease presentation amongst ASD syndromes creates challenges for correct diagnosis and classification. The use of animal models has therefore proved to be a robust approach for unravelling this complex genotypic and phenotypic heterogeneity. However, despite these successes, it is clear that additional genes that underlie several ASD syndromes remain unidentified. Here, we report the characterisation of a novel mouse model of ASD. Conditional deletion of during eye development leads to a premature upregulation of mTORC1 activity within the ciliary margin, periocular mesenchyme and lens epithelium. This aberrant mTORC1 signalling within the ciliary margin in particular leads to a reduction in the number of cells that express Pax6, and Sustained mTORC1 signalling also induces a decrease in ciliary margin progenitor cell proliferation and a consequent failure of ciliary body and iris development in postnatal animals. Our study therefore identifies as a novel candidate ASD gene. Furthermore, the -ablated mouse model also provides a valuable resource for future studies concerning the molecular mechanisms underlying ASD and acts as a platform for evaluating therapeutic approaches for the treatment of visual disorders.
眼睛前段角膜、晶状体、睫状体和虹膜的发育涉及源自视杯睫状缘、覆盖其上的眼周间充质和晶状体上皮的细胞之间的协调相互作用。前段发育异常（ASD）包括一系列影响这些前段组织的发育综合征。ASD病症是由显性遗传基因突变引起的，分别导致以无虹膜和Axenfeld-Rieger综合征为最佳例证的眼部特异性和全身性发育异常形式。ASD综合征之间疾病表现的广泛临床重叠给正确诊断和分类带来了挑战。因此，使用动物模型已被证明是揭示这种复杂的基因型和表型异质性的有力方法。然而，尽管取得了这些成功，但很明显，几种ASD综合征背后的其他基因仍未被鉴定出来。在这里，我们报告了一种新型ASD小鼠模型的特征。在眼睛发育过程中条件性缺失会导致睫状缘、眼周间充质和晶状体上皮内mTORC1活性过早上调。特别是睫状缘内这种异常的mTORC1信号传导会导致表达Pax6的细胞数量减少，并且持续的mTORC1信号传导还会诱导睫状缘祖细胞增殖减少，从而导致出生后动物的睫状体和虹膜发育失败。因此，我们的研究将鉴定为一种新型的ASD候选基因。此外，基因敲除小鼠模型还为未来关于ASD潜在分子机制的研究提供了宝贵资源，并作为评估治疗视觉障碍治疗方法的平台。
