Unexpected Transcriptional Activity of the Human VMD2 Promoter in Retinal Development

Abstract

Vitelliform macular dystrophy (VMD) is associated with mutations in the VMD2 gene, which encodes a chloride channel protein and is thought to be preferentially expressed in the retinal pigmented epithelium (RPE). In an effort to establish an inducible gene knockout system for the RPE, we recently used a 3.0-kb human VMD2 promoter to direct the expression of a reverse tetracycline-inducible system controlled Cre recombinase in transgenic mice. Although Cre function was localized to the RPE in most VMD2-cre mouse lines, Cre activity was also identified in neural retina in approximately half of the transgenic lines. In two VMD2-cre mouse lines, Cre activity was predominately localized to retinal Müller cells. This surprising expression pattern is likely caused by the transcriptional activity of our transgene system during retinal development. Therefore, our results suggest that transcription of VMD2 gene may occur in progenitors of Müller cells. The two VMD2-cre mouse lines that demonstrated Cre activity specifically in the RPE or predominantly in the Müller cells were fully characterized. These VMD2-cre mice are potentially useful for dissecting cellular mechanisms of age-related macular degeneration or diabetic retinopathy, two leading causes of blindness with high relevance to gene expression in the RPE or Müller cells.