Impairment of photoreceptor ribbon synapses in a novel Pomt1 conditional knockout mouse model of dystroglycanopathy

Sci Rep. 2018 Jun 4;8(1):8543. doi: 10.1038/s41598-018-26855-x.

Abstract

Hypoglycosylation of α-dystroglycan (α-DG) resulting from deficiency of protein O-mannosyltransferase 1 (POMT1) may cause severe neuromuscular dystrophies with brain and eye anomalies, named dystroglycanopathies. The retinal involvement of these disorders motivated us to generate a conditional knockout (cKO) mouse experiencing a Pomt1 intragenic deletion (exons 3-4) during the development of photoreceptors, mediated by the Cre recombinase expressed from the cone-rod homeobox (Crx) gene promoter. In this mouse, retinal α-DG was unglycosylated and incapable of binding laminin. Retinal POMT1 deficiency caused significant impairments in both electroretinographic recordings and optokinetic reflex in Pomt1 cKO mice, and immunohistochemical analyses revealed the absence of β-DG and of the α-DG-interacting protein, pikachurin, in the outer plexiform layer (OPL). At the ultrastructural level, noticeable alterations were observed in the ribbon synapses established between photoreceptors and bipolar cells. Therefore, O-mannosylation of α-DG in the retina carried out by POMT1 is crucial for the establishment of proper synapses at the OPL and transmission of visual information from cones and rods to their postsynaptic neurons.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Dystroglycans / genetics
  • Dystroglycans / metabolism
  • Electroretinography*
  • Glycosylation
  • Mannosyltransferases* / genetics
  • Mannosyltransferases* / metabolism
  • Mice
  • Mice, Knockout
  • Retinal Cone Photoreceptor Cells* / metabolism
  • Retinal Cone Photoreceptor Cells* / pathology
  • Retinal Rod Photoreceptor Cells / metabolism
  • Retinal Rod Photoreceptor Cells / pathology
  • Synapses* / genetics
  • Synapses* / metabolism
  • Synapses* / pathology
  • Walker-Warburg Syndrome* / genetics
  • Walker-Warburg Syndrome* / metabolism
  • Walker-Warburg Syndrome* / pathology

Substances

  • Dag1 protein, mouse
  • Dystroglycans
  • Mannosyltransferases
  • protein O-mannosyltransferase