Chen Yu, Carlson Eric C, Chen Zhi-Yi, Hamik Anne, Jain Mukesh K, Dunwoodie Sally L, Yang Yu-Chung
Department of Biochemistry and Cancer Center, Case Western Reserve University School of Medicine, Cleveland, OH 44106, USA.
Dev Biol. 2009 Oct 1;334(1):243-52. doi: 10.1016/j.ydbio.2009.07.028. Epub 2009 Jul 24.
Cited2 is an important transcriptional cofactor involved in multiple organ development. Gene profile analysis has identified Cited2 as one of the transcription factors expressed at high levels in adult mouse cornea. To address the function of Cited2 in corneal morphogenesis, we deleted Cited2 in surface ectoderm derived ocular structures including cornea by crossing Cited2-floxed mice with Le-Cre transgenic mice. Cited2(flox/flox);Le-Cre(+) eyes invariably displayed corneal opacity and developed spontaneous corneal neovascularization at older age. Fewer layers of corneal epithelial cells and the absence of cytokeratin 12 (K12) expression featured Cited2 deficient postnatal and adult eyes. Cited2 deficient cornea exhibited impaired healing in response to corneal epithelial debridement by manifesting abnormal histology, lack of K12 expression and corneal neovascularization. Moreover, mechanistic studies suggest that Cited2 may play a role in corneal morphogenesis in part through modulating the expression of Pax6 and Klf4. Collectively, these findings demonstrate a novel function of Cited2 in postnatal corneal morphogenesis and maintenance. Our study will help better understand the molecular mechanisms involved in corneal biology, and more importantly, it may provide a valuable animal model for testing therapeutics in the treatment of corneal disorders, especially blindness as a result of corneal epithelial cell deficiency.
Cited2是一种参与多器官发育的重要转录辅因子。基因谱分析已确定Cited2是成年小鼠角膜中高表达的转录因子之一。为了研究Cited2在角膜形态发生中的功能，我们通过将Cited2基因条件性敲除小鼠与Le-Cre转基因小鼠杂交，在包括角膜在内的表面外胚层来源的眼结构中删除Cited2。Cited2(flox/flox);Le-Cre(+)小鼠的眼睛总是表现出角膜混浊，并在老年时出现自发性角膜新生血管。Cited2基因缺陷的出生后和成年小鼠眼睛的角膜上皮细胞层数减少，且缺乏细胞角蛋白12（K12）表达。Cited2基因缺陷的角膜在角膜上皮清创后愈合受损，表现为组织学异常、缺乏K12表达和角膜新生血管。此外，机制研究表明，Cited2可能部分通过调节Pax6和Klf4的表达在角膜形态发生中发挥作用。总体而言，这些发现证明了Cited2在出生后角膜形态发生和维持中的新功能。我们的研究将有助于更好地理解角膜生物学的分子机制，更重要的是，它可能为测试治疗角膜疾病，特别是因角膜上皮细胞缺乏导致的失明的疗法提供有价值的动物模型。
