Corneal diseases such as infections and injury are major causes of blindness with alterations in both epithelium and stroma leading to the loss of corneal transparency. Co-factors of LIM (Clims; also called Ldb and Nli), which regulate transcription of target genes by associating with DNA-binding proteins, are highly expressed in epithelia. To study their function in epithelial cells, we expressed a dominant negative Clim under control of the keratin 14 promoter in mice (K14-DN-Clim mice). In addition to developing mild hair loss, these mice postnatally develop blindness from progressive increase in cloudiness of the cornea. Histologically, the corneal epithelium undergoes a change towards epidermis-like epithelium, and vasculature and inflammatory cells invade the stroma. Our hypothesis is that Clims are required for preventing the corneal epithelial cells from converting to an epidermal fate, a property that is blocked in K14-DN-Clim mice. To test this hypothesis and to understand in greater detail the pathogenesis of corneal abnormalities in K14-DN-Clim mice, we propose the following Specific Aims: #1. To identify the initial morphological changes and characterize progression of corneal abnormalities in the K14-DN-Clim mice. #2. To use gene expression profiling to gain understanding into molecular mechanisms of corneal abnormalities in K14-DN-Clim mice. #3. To identify transcriptional complexes that associate with Clim2 in corneal epithelial cells. This new mouse model may be important for understanding the molecular pathways that prevent keratinization of corneal epithelium and vacularization of corneal stroma. In addition, characterization of the K14-DN-Clim mice may provide insights into the pathogenesis of corneal causes of blindness and provide a potential model to test therapeutic approaches. ? ?
| Yu, Zhengquan; Bhandari, Ambica; Mannik, Jaana et al. (2008) Grainyhead-like factor Get1/Grhl3 regulates formation of the epidermal leading edge during eyelid closure. Dev Biol 319:56-67 |
| Xu, Xiaoman; Mannik, Jaana; Kudryavtseva, Elena et al. (2007) Co-factors of LIM domains (Clims/Ldb/Nli) regulate corneal homeostasis and maintenance of hair follicle stem cells. Dev Biol 312:484-500 |
