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Amanda Grace Kautzman, Patrick William Keeley, Michael M Nahmou, Gabriel Luna, Steven K Fisher, Benjamin E Reese; Sox2 deficiency leads to the abnormal development of retinal astrocytes and vasculature in the mouse. Invest. Ophthalmol. Vis. Sci. 2017;58(8):5394.
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© ARVO (1962-2015); The Authors (2016-present)
Sox2 belongs to the large SRY-related HMG-box transcription factor family and is best recognized for its role in early development by maintaining embryonic stem cell pluripotency. Sox2 is a critical gene for eye development, and its expression is maintained in mature glial cells in the retina, in particular, the astrocytes, yet its specific role in these cells has yet to be explored. The present study has examined a potential role for Sox2 in the development of astrocytes within the mouse retina.
GFAP-Cre mice and Sox2-flox mice were used to generate Sox2 conditional knockout mice (CKO). Control (CTL) animals were CKO littermates that were Cre-negative and/or Sox2-wildtype. Retinal wholemounts were immunolabeled using antibodies to Pax2, Sox2, GFAP, and/or Collagen IV, to reveal the astrocytes and retinal vasculature. Wholemount retinal mosaics were generated by registering individual high-resolution 40X confocal images together. Vascular branch points were manually counted from 8 peripheral and 8 central images per retina.
Developing Pax2-positive astrocytes in CKO retinas migrate normally into the retina from the optic nerve head around the time of birth, and continue to the retinal periphery during the first postnatal week. Their maturation, however, is disrupted relative to CTL retinas, as evidenced by their conspicuously late central-to-peripheral upregulation in GFAP expression. Astrocytic abnormalities persisted into adulthood, including a regional loss of GFAP and the presence of aberrant sprouting of processes into the inner plexiform layer.Given that astrocytes provide a scaffold for retinal blood vessel formation, we examined the developing vasculature and found significant delays to vascular advancement across the central-to-peripheral axis in CKO animals that correlated to the delay in GFAP upregulation. Vascular defects also persisted into maturity, resulting in a significant reduction in vasculature branch point frequency of CKO when compared to controls.
These results implicate Sox2 as an important player in the development of retinal astrocytes, and suggest that their delayed maturation, indicated by their late upregulation of GFAP, is sufficient to perturb angiogenesis, yielding lasting changes into maturity.
This is an abstract that was submitted for the 2017 ARVO Annual Meeting, held in Baltimore, MD, May 7-11, 2017.
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