Retinal pigment epithelium-specific CLIC4 mutant is a mouse model of dry age-related macular degeneration.

Age-related macular degeneration (AMD) is the leading cause of blindness among the elderly. Dry AMD has unclear etiology and no treatment. Lipid-rich drusen are the hallmark of dry AMD. An AMD mouse model and insights into drusenogenesis are keys to better understanding of this disease. Chloride intracellular channel 4 (CLIC4) is a pleomorphic protein regulating diverse biological functions. Here we show that retinal pigment epithelium (RPE)-specific Clic4 knockout mice exhibit a full spectrum of functional and pathological hallmarks of dry AMD. Multidisciplinary longitudinal studies of disease progression in these mice support a mechanistic model that links RPE cell-autonomous aberrant lipid metabolism and transport to drusen formation.

Retinal ganglion cell defects cause decision shifts in visually evoked defense responses.

A variety of visual cues can trigger defensive reactions in mice and other species. In mice, looming stimuli that mimic an approaching aerial predator elicit flight or freezing reactions, while sweeping stimuli that mimic an aerial predator flying parallel to the ground typically elicit freezing. The retinal ganglion cell (RGC) types involved in these circuits are largely unknown. We previously discovered that loss of RGC subpopulations in Brn3b knockout mice results in distinct visual response deficits. Here, we report that retinal or global loss of Brn3b selectively ablates the fleeing response to looming stimuli while leaving the freeze response intact. In contrast, freezing responses to sweeping stimuli are significantly affected. Genetic manipulations removing three RGC subpopulations (Brn3a+ betta RGCs, Opn4+Brn3b+, and Brn3c+Brn3b+ RGCs) result in milder phenocopies of Brn3b knockout response deficits. These findings show that flight and freezing responses to distinct visual cues are mediated by circuits that can already be separated at the level of the retina, potentially by enlisting dedicated RGC types.NEW & NOTEWORTHY Flight and freezing response choices evoked by visual stimuli are controlled by brain stem and thalamic circuits. Genetically modified mice with loss of specific retinal ganglion cell (RGC) subpopulations have altered flight versus freezing choices in response to some but not other visual stimuli. This finding suggests that "threatening" visual stimuli may be computed already at the level of the retina and communicated via dedicated pathways (RGCs) to the brain.