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C.-H. Xia, H. Liu, D. Cheung, M. Wang, X. Gong; LRP5 Is Essential for the Development of Retinal Vasculature. Invest. Ophthalmol. Vis. Sci. 2008;49(13):4005. doi: https://doi.org/.
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© ARVO (1962-2015); The Authors (2016-present)
To identify the causative gene mutation of a new mouse recessive mutant line that develops attenuated and hyperpermeable retinal vessels, recapitulating some pathological features of familial exudative vitreoretinopathy (FEVR) in human patients. To elucidate how the development of retinal vasculature is regulated by the low-density lipoprotein receptor-related protein 5 (LRP5), an indispensable element of the canonical Wnt/beta-catenin signaling pathway by acting as a Wnt coreceptor.
DNA sequencing of RT-PCR product from mutant retina mRNA was performed to determine the causative gene mutation. Fundus examination, fluorescein angiography, immunostaining, 3-dimensional retinal vasculature reconstruction and transmission electron microscopy were carried out to evaluate the molecular and cellular alterations of retinal vasculature in mutant animals.
Causative gene mutation was mapped to a region close to the LRP5 gene. DNA sequencing revealed a single nucleotide insertion in the exon 23 of LRP5 gene, causing a frame shift and resulting in the replacement of the C-terminal 39 amino acid residues by 20 new amino acids. Immunostaining and 3-dimensional reconstructions of retinal vasculature confirmed attenuated retinal vessels, especially the loss of capillaries in the outer plexiform layer. Ultrastructural data further showed that some of capillaries in the inner plexiform layer lacked lumen structure.
Recent genetic studies show that LRP5 mutations are linked to FEVR in humans. The retina phenotypes of this recessive mouse mutation are likely resulted from this single nucleotide insertion in the LRP5 gene. This mutation eliminates the last three PPP(S/T)P repeats in the LRP5 cytoplasmic domain that is important for mediating the Wnt/beta-catenin signaling based on the studies in vitro. Our current work indicates that LRP5 is essential for the development of retinal vasculature, especially the maturation and/or lumen formation of retinal capillaries, and that this C-terminal truncated LRP5 mutant protein is unable to mediate the downstream signaling in vivo.
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