Abstract
Abstract: :
Purpose: A transgenic mouse expressing the herpes virus 1 thymidine kinase (HSV1-TK) gene under the control of the myelin basic protein gene promoter (MBP-TK) has been recently developed to induce dysmyelination as a consequence of the selective ablation of oligodendrocytes. Cytotoxicity is induced by administration in transgenic animals of 1-(2-deoxy-2-fluoro-b-d-arabinofuranosyl)-5-iodouracil (FIAU), a nucleoside analogue (Mathis et al., 2000). Transgenic MBP-TK mice, treated with FIAU from postnatal day 1 (PN1) to PN2 or PN6, develop an aberrant postnatal development of the retina leading to modified cell type differentiation and subsequent photoreceptor degeneration. Methods: PN1 transgenic MBP-TK mice and their wild type littermates were treated daily with FIAU (40 mg/kg) for 1, 3 or 5 days. Retinal cells were examined by immunohistochemistry at different times between PN2 and PN21 using antibodies specific for each cell type. Results: Importantly, regardless of the length of the treatment a similar retinal phenotype is observed, characterized by an increase of amacrine cells only in transgenic mice. At PN7, 14 and 21, and depending of the treatment length, a reduced PKC-positive cell number was observed (85, 70 or 35 % respectively), suggesting that the transgene might be ectopically expressed in precursors of bipolar cells. At PN7, photoreceptor differentiation was normally achieved, but a progressive degeneration of these cells occured after PN10, to reach values very similar to those of bipolar cells at PN21. A disorganization of Müller glia was present from PN5, thus preceding photoreceptor degeneration and suggesting a possible correlation between these two events. To analyze the mechanism(s) responsible for this phenotype we are currently searching the cells expressing the transgenic construct, since the retina is normally devoid of oligodendrocytes as well as analyzing the phenotype in greater details. Preliminar experiments exclude a possible role of the dysmyelinated optic nerve in the observed phenotype. Conclusions: We describe here a novel model of retinal degeneration in which alteration of the postnatal development and early photoreceptor cell death are observed. Loss of bipolar cells as well as the onset of synaptogenesis correlate with photoreceptor degeneration showing a tight interaction between these two cell types during postnatal retinal maturation. The lower bipolar and higher amacrine cell numbers together with the intrinsic retinal transgene expression suggest the induction of common cellular and molecular events involved in their differentiation.
Keywords: 554 retina • 517 photoreceptors • 385 degenerations/dystrophies