Glial transcytosis of a photoreceptor‐secreted signaling protein, retinoschisin

Abstract

In vitro studies have clearly shown that signaling/guidance proteins can diffuse to their targets. However, it is unclear whether they can travel by diffusion in vivo, or if they are distributed in the tissue by an active mechanism. Retinoschisin, a signaling molecule related to neuropilins, is synthesized and secreted by photoreceptor cells in the outer retina; then it interacts with inner retinal cells contributing to synaptic organization and optic nerve fiber integrity. We developed an assay to examine how retinoschisin, which is secreted a distance away, reaches its inner retinal targets. We found that retinoschisin is preferentially taken up and carried into the inner retina from the retinal outer border (the photoreceptor side) by Müller cells (the main glial cells of the vertebrate retina). This transcytosis is disrupted by DL-alpha-aminoadipic acid, a Müller cell/glia-specific toxin. Our results suggest that glial uptake/transcytosis can provide an effective and precise alternative for distributing signaling molecules in the nervous system.

Retinoschisin, a New Binding Partner for L-type Voltage-gated Calcium Channels in the Retina

“…In addition, the distribution of retinoschisin protein in chick retina (Fig. 1) is very similar to the pattern described in mammals (8,15,33). These results indicate that retinoschisin is very important in retina function and physiology across species.…”

“…We also found that the distribution of retinoschisin protein in the chick retina (Fig. 1A) was similar to that in mammals (8,15,33). The distribution of retinoschisin protein was most prominent on the photoreceptor outer and inner segments (OS/IS), whereas outer and inner plexiform layers (OPL and IPL) also showed heavier staining (Fig.…”

“…Retinoschisin is believed to play an important role in cell-cell adhesion in development and maintenance of retinal cytoarchitecture (7,8,15). However, the concentration of retinoschisin remains high in the photoreceptor layer in adults (33), and recent evidence shows that the pineal glands in rodents and humans also express retinoschisin (36).…”

“…Mutations in retinoschisin (RS1) cause X-linked retinoschisis (XLRS), a retinal dystrophy that features disorganization of retinal cell layers, disruption of the synaptic structures and neurotransmission between photoreceptors and bipolar cells, and progressive degeneration of rod and cone photoreceptor cells (7, 10 -14). Hence, retinoschisin is believed to play an important role in the development and maintenance of retinal cytoarchitecture (7,8,15). An interesting clinical aspect of XLRS is that it shares several quantifiable features with X-linked incomplete congenital stationary night blindness (XLCSNB), which is an inherited retinal dystrophy with a mutation in the L-type VGCC␣1 subunit gene (16,17).…”

Pediatric Hereditary Macular Degenerations

“…Müller glial cells play a role in distributing RS1 throughout the retina through a process of transcytosis [128]. While RS1 appears to be synthesized by all retinal neurons during development [125], other experiments have shown that retinoschisin, synthesized and secreted into the subretinal space by photoreceptors, is endocytosed by the apical microvilli of Müller cells, which then transport it internally and secrete it throughout the inner and outer retina at its focus sites in the mature retina [49,125,127,128]. This may be a mechanism to supplement retinoschisin expression throughout the retina.…”