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Abstract
Type IV collagens are the most abundant proteins in basement membranes. Distinct genes
encode each of six isoforms, alpha1(IV) through alpha6(IV), which assemble into one
of three characteristic heterotrimers. Disease-causing mutations in each of the six
genes are identified in humans or mice and frequently include diverse ocular pathogenesis
that encompass common congenital and progressive blinding diseases, such as optic
nerve hypoplasia, glaucoma, and retinal degeneration. Understanding where and when
collagen IV molecules are expressed is important because it defines limits for the
location and timing of primary pathogenesis. Although localization of collagen IV
isoforms in developed human eyes is known, the spatial and temporal distribution of
type IV collagens throughout ocular development has not been determined in humans
or in mice. Here, we use isoform-specific monoclonal antibodies to systematically
reveal the localization of all six collagen IV isoforms in developing mouse eyes.
We found that alpha1(IV) and alpha2(IV) always co-localized and were ubiquitously
expressed throughout development. alpha3(IV) and alpha4(IV) also always co-localized
but in a much more spatially and temporally specific manner than alpha1(IV) and alpha2(IV).
alpha5(IV) co-localized both with alpha3(IV)/alpha4(IV), and with alpha6(IV), consistent
with alpha5(IV) involvement in two distinct heterotrimers. alpha5(IV) was present
in all basement membranes except those of the vasculature. alpha6(IV) was not detected
in vasculature or in Bruch's membrane, indicating that alpha5(IV) in Bruch's membrane
is part of the alpha3alpha4alpha5 heterotrimer. This comprehensive analysis defines
the spatial and temporal distribution of type IV collagen isoforms in the developing
eye, and will contribute to understanding the mechanisms underlying collagen IV-related
ocular diseases that collectively lead to blindness in millions of people worldwide.