Abstract
Purpose :
Mutations in human LAMB2 cause Pierson Syndrome typified by kidney and ocular dysgenesis and early death; conventional deletion of murine Lamb2causes similar defects. The murine retinal phenotype shows that laminins regulate progenitor behavior, synapse formation, Müller cell polarity and vascular development, but potential systemic effects on muscle and kidney complicates the interpretation. Here, we produce a retina-specificLamb2deletion that results in a novel, progressive retinal degeneration.
Methods :
dkk3-cre; Lamb2loxP/loxP were generated by crossing Lamb2loxP/+or Lamb2 loxP/loxPfemales with dkk3-cre;Lamb2loxP/+males; littermate Lamb2loxP/loxPwere used as controls. Recombination was confirmed with a Rosa reporter. OCT scans were obtained at P15 (n=2) and 1 (n=4), 5 (n=4) and 8 (n=1) months postnatal; ERGs were obtained from the same mice within a week. Retinal organization was studied histologically.
Results :
In contrast to whole animal deletions, conditional KO mice live a normal life span and thrive. OCT scans show abnormal structural changes starting at P15 that worsen with age. Abnormalities include fibrotic formations on the vitreal border that progressively extend into the vitreal body; progressive retinal folding and thinning; and, in severe cases, retinal detachment. Histologic examination of the retina demonstrated a progressive loss of tissue organization, Müller cell hypertrophy and disorganization as well as extrusion into the vitreal body. ILM integrity is compromised as judged by various matrix markers. Retinal astrocyte distribution was disrupted with a concomitant vascular disruption and persistence of the hyaloid vessels to 1 month postnatal. Age-related disruption in the ONL was observed, along with disruptions in synaptic morphology, specifically a progressive loss of integrity in the photoreceptor-bipolar synapse. ERG recordings demonstrated progressive photoreceptor degeneration starting at 1 month. Both the a- and b-waves were reduced significantly (p< 0.001), with the b-wave more profoundly affected.
Conclusions :
Conditional disruption of the Lamb2 gene in the retina results in a progressive disruption of retinal structure and function; the knockout profoundly disrupts the organization of the major retinal glial cells (Müller cells and astrocytes) and results in a process that mimics features of both proliferative vitreoretinopathy and retinoschisis.
This abstract was presented at the 2019 ARVO Annual Meeting, held in Vancouver, Canada, April 28 - May 2, 2019.