Abstract
Primary loss of photoreceptors caused by diseases such as retinitis pigmentosa is one of the main causes of blindness worldwide. To study such diseases, rodent models of N-methyl-N-nitrosourea (MNU)-induced retinal degeneration are widely used. As zebrafish (Danio rerio) are a popular model system for visual research that offers persistent retinal neurogenesis throughout the lifetime and retinal regeneration after severe damage, we have established a novel MNU-induced model in this species. Histology with staining for apoptosis (TUNEL), proliferation (PCNA), activated Müller glial cells (GFAP), rods (rhodopsin) and cones (zpr-1) were performed. A characteristic sequence of retinal changes was found. First, apoptosis of rod photoreceptors occurred 3 days after MNU treatment and resulted in a loss of rod cells. Consequently, proliferation started in the inner nuclear layer (INL) with a maximum at day 8, whereas in the outer nuclear layer (ONL) a maximum was observed at day 15. The proliferation in the ONL persisted to the end of the follow-up (3 months), interestingly, without ongoing rod cell death. We demonstrate that rod degeneration is a sufficient trigger for the induction of Müller glial cell activation, even if only a minimal number of rod cells undergo cell death. In conclusion, the use of MNU is a simple and feasible model for rod photoreceptor degeneration in the zebrafish that offers new insights into rod regeneration.
Highlights
Zebrafish (Danio rerio) provide an important model system in visual research, especially due to their cone-rich retina and persistent retinal neurogenesis throughout the zebrafish lifetime [1,2,3,4,5,6]
Muller glial cells located in the inner nuclear layer (INL) of the retina are able to generate rod progenitors, which reside in the outer nuclear layer (ONL) [7]
Barnados et al have investigated these proliferating cells in an ultra-high-intensity light treatment model in transgenic zebrafish in which Muller glial cells expressed green fluorescence protein [18,19]. They concluded that the proliferating cells in the INL were de-differentiated Muller glial cells and are able to migrate from the INL into the ONL forming rod progenitors and thereby regenerating photoreceptor cells [7,18,19]
Summary
Zebrafish (Danio rerio) provide an important model system in visual research, especially due to their cone-rich retina and persistent retinal neurogenesis throughout the zebrafish lifetime [1,2,3,4,5,6]. Barnados et al have investigated these proliferating cells in an ultra-high-intensity light treatment model in transgenic zebrafish in which Muller glial cells expressed green fluorescence protein [18,19] They concluded that the proliferating cells in the INL were de-differentiated Muller glial cells and are able to migrate from the INL into the ONL forming rod progenitors and thereby regenerating photoreceptor cells [7,18,19]. Injection and in vivo electroporation of PCNA morpholinos inhibited Muller glial cell proliferation and blocked regeneration of the retina These data suggest that Muller glial cell division is necessary for proper photoreceptor regeneration in the light-damaged zebrafish retina and that Muller glial cells serve as the source of neuronal progenitor cells [15]. Muller glial cells have the potential to regenerate neurons of the inner retina, as observed in a model of inner retina destruction with intravitreal injection of ouabain [14] or after optic nerve crush [17]
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