Impairment of Visual Function and Retinal ER Stress Activation in Wfs1-Deficient Mice

Abstract

Wolfram syndrome is an early onset genetic disease (1/180,000) featuring diabetes mellitus and optic neuropathy, associated to mutations in the WFS1 gene. Wfs1−/− mouse model shows pancreatic beta cell atrophy, but its visual performance has not been investigated, prompting us to study its visual function and histopathology of the retina and optic nerve. Electroretinogram and visual evoked potentials (VEPs) were performed in Wfs1−/− and Wfs1+/+ mice at 3, 6, 9 and 12 months of age. Fundi were pictured with Micron III apparatus. Retinal ganglion cell (RGC) abundance was determined from Brn3a immunolabeling of retinal sections. RGC axonal loss was quantified by electron microscopy in transversal optic nerve sections. Endoplasmic reticulum stress was assessed using immunoglobulin binding protein (BiP), protein disulfide isomerase (PDI) and inositol-requiring enzyme 1 alpha (Ire1α) markers. Electroretinograms amplitudes were slightly reduced and latencies increased with time in Wfs1−/− mice. Similarly, VEPs showed decreased N+P amplitudes and increased N-wave latency. Analysis of unfolded protein response signaling revealed an activation of endoplasmic reticulum stress in Wfs1 −/− mutant mouse retinas. Altogether, progressive VEPs alterations with minimal neuronal cell loss suggest functional alteration of the action potential in the Wfs1 −/− optic pathways.

Wfs1- deficient rats develop primary symptoms of Wolfram syndrome: insulin-dependent diabetes, optic nerve atrophy and medullary degeneration

“…It is not known whether retinal gliosis is a direct result of WFS1 dysfunction in the retina or is caused by the hyperglycaemia that is seen in older mutant animals. Levels of ER stress markers were also increased in the retinas of Wfs1-ex5-KO232 rats, in agreement with reported increases of ER stress in the retinas of Wfs1-KO mice 26 . Increases in the expression of pIRE1α in the inner plexiform layer of Wfs1-ex5-KO232 rats can be attributed to increased ER stress in ganglion cells as the expression of WFS1 was found in these cells 26 .…”

Layer 2/3 pyramidal cells in the medial prefrontal cortex moderate stress induced depressive behaviors

“…Our demonstration that Wfs1 is required for normal ER function in layer 2/3 pyramidal cells in the mPFC and that these cells moderate depressive behaviors in response to stress, raises two issues regarding Wfs1 . First, given previous studies documenting an essential function for Wfs1 in pancreatic β cells ( Ishihara et al, 2004 ; Fonseca et al, 2005 ) and the retina ( Bonnet Wersinger et al, 2014 ), and detailed biochemical studies demonstrating that WFS1 negatively regulates ER stress signaling through ATF6α ( Fonseca et al, 2010 ), it seems probable that cell types expressing Wfs1 in the brain also require its function to regulate ER stress. In the case of pancreatic β cells, it is thought that WFS1 tightly controls ER stress to regulate insulin production in response to frequent fluctuations of blood glucose.…”

Endoplasmic Reticulum Stress in Hearing Loss

“…In other words, WS-associated WFS1 mutations lead to loss of function of WFS1. Consistently, Wfs1 gene knockdown in cultured cells or Wfs1 gene disruption in mice caused elevated UPR and increased ER-stress-induced apoptosis [63,[70][71][72]. It is worth noticing that Wfs1 disruption has different effects on different tissues in mice.…”

“…It is worth noticing that Wfs1 disruption has different effects on different tissues in mice. In Wfs1 −/− mice, all three UPR pathways are activated in pancreatic cells, whereas only the IRE1α pathway is activated in the retina, and no ER stress is activated in other tissues examined such as the heart, skeletal muscle, and brown adipose tissue [71,72]. WFS1 is widely expressed in multiple cell types in the inner ear, including HCs, SGCs, various supporting cells (SCs), and lateral wall fibrocytes [73].…”