Developmental distribution of collagen IV isoforms and relevance to ocular diseases.
Developmental distribution of collagen IV isoforms and relevance to ocular diseases.
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DOI：
10.1016/j.matbio.2009.02.004
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发表时间：
2009-05
期刊：
影响因子：
--
通讯作者：
Gould DB
中科院分区：
文献类型：
--
作者：
Bai X;Dilworth DJ;Weng YC;Gould DB
IV 型胶原蛋白是基底膜中最丰富的蛋白质。不同的基因编码 α1(IV) 至 α6(IV) 六种亚型中的每一种，它们组装成三种特征异源三聚体之一。在人类或小鼠中发现了这六个基因中每一个的致病突变，这些突变通常包括多种眼部发病机制，包括常见的先天性和进行性致盲疾病，例如视神经发育不全、青光眼和视网膜变性。了解 IV 型胶原蛋白分子表达的地点和时间非常重要，因为它定义了主要发病机制的位置和时间的限制。尽管 IV 型胶原同种型在发育的人眼中的定位是已知的，但 IV 型胶原在整个眼部发育过程中的空间和时间分布尚未在人类或小鼠中确定。在这里，我们使用异构体特异性单克隆抗体系统地揭示了所有六种胶原蛋白 IV 异构体在发育中的小鼠眼睛中的定位。我们发现α1(IV)和α2(IV)总是共定位并且在整个发育过程中普遍表达。 α3(IV) 和 α4(IV) 也总是共定位，但在空间和时间上比 α1(IV) 和 α2(IV) 更具特异性。 α5(IV) 与 α3(IV)/α4(IV) 和 α6(IV) 共定位，这与 α5(IV) 参与两个不同的异源三聚体一致。 α5(IV) 存在于除脉管系统之外的所有基底膜中。在脉管系统或布鲁赫膜中未检测到α6(IV)，表明布鲁赫膜中的α5(IV)是α3α4α5异三聚体的一部分。这项综合分析定义了 IV 型胶原同种型在发育中眼睛中的空间和时间分布，并将有助于了解 IV 型胶原蛋白相关眼部疾病的潜在机制，这些疾病共同导致全世界数百万人失明。
Type IV collagens are the most abundant proteins in basement membranes. Distinct genes encode each of six isoforms, α1(IV) through α6(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 α1(IV) and α2(IV) always co-localized and were ubiquitously expressed throughout development. α3(IV) and α4(IV) also always co-localized but in a much more spatially and temporally specific manner than α1(IV) and α2(IV). α5(IV) co-localized both with α3(IV)/α4(IV), and with α6(IV), consistent with α5(IV) involvement in two distinct heterotrimers. α5(IV) was present in all basement membranes except those of the vasculature. α6(IV) was not detected in vasculature or in Bruch's membrane, indicating that α5(IV) in Bruch's membrane is part of the α3α4α5 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.