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βA3/A1-crystallin is required for proper astrocyte template formation and vascular remodeling in the retina

Author:
Sinha, Debasish, Valapala, Mallika, Bhutto, Imran, Patek, Bonnie, Zhang, Cheng, Hose, Stacey, Yang, Fang, Cano, Marisol, Stark, Walter J., Lutty, Gerard A., Zigler, J. Samuel, Wawrousek, Eric F.
Source:
Transgenic research 2012 v.21 no.5 pp. 1033-1042
ISSN:
0962-8819
Subject:
abnormal development, animal models, astrocytes, endothelial cells, fluorescein, gene overexpression, genes, mice, mutation, nerve tissue, rats, retina
Abstract:
Nuc1 is a spontaneous rat mutant resulting from a mutation in the Cryba1 gene, coding for βA3/A1-crystallin. Our earlier studies with Nuc1 provided novel evidence that astrocytes, which express βA3/A1-crystallin, have a pivotal role in retinal remodeling. The role of astrocytes in the retina is only beginning to be explored. One of the limitations in the field is the lack of appropriate animal models to better investigate the function of astrocytes in retinal health and disease. We have now established transgenic mice that overexpress the Nuc1 mutant form of Cryba1, specifically in astrocytes. Astrocytes in wild type mice show normal compact stellate structure, producing a honeycomb-like network. In contrast, in transgenics over-expressing the mutant (Nuc1) Cryba1 in astrocytes, bundle-like structures with abnormal patterns and morphology were observed. In the nerve fiber layer of the transgenic mice, an additional layer of astrocytes adjacent to the vitreous is evident. This abnormal organization of astrocytes affects both the superficial and deep retinal vascular density and remodeling. Fluorescein angiography showed increased venous dilation and tortuosity of branches in the transgenic retina, as compared to wild type. Moreover, there appear to be fewer interactions between astrocytes and endothelial cells in the transgenic retina than in normal mouse retina. Further, astrocytes overexpressing the mutant βA3/A1-crystallin migrate into the vitreous, and ensheath the hyaloid artery, in a manner similar to that seen in the Nuc1 rat. Together, these data demonstrate that developmental abnormalities of astrocytes can affect the normal remodeling process of both fetal and retinal vessels of the eye and that βA3/A1-crystallin is essential for normal astrocyte function in the retina.
Agid:
585981