We have identified a mouse recessive mutation that leads to attenuated and hyperpermeable retinal vessels, recapitulating some pathological features of familial exudative vitreoretinopathy (FEVR) in human patients. DNA sequencing reveals a single nucleotide insertion in the gene encoding the low-density lipoprotein receptor-related protein 5 (LRP5), causing a frame shift and resulting in the replacement of the C-terminal 39 amino acid residues by 20 new amino acids. This change eliminates the last three PPP(S/T)P repeats in the LRP5 cytoplasmic domain that are important for mediating Wnt/beta-catenin signaling. Thus, mutant LRP5 protein is probably unable to mediate its downstream signaling. Immunostaining and three-dimensional reconstructions of retinal vasculature confirm attenuated retinal vessels. Ultrastructural data further reveal that some capillaries lack lumen structure in the mutant retina. We have also verified that LRP5 null mice develop similar alterations in the retinal vasculature. This study provides direct evidence that LRP5 is essential for the development of retinal vasculature, and suggests a novel role played by LRP5 in capillary maturation. LRP5 mutant mice can be a useful model to explore the clinical manifestations of FEVR.

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Different mutations of ␣3 connexin (Cx46 or Gja8) and ␣8 connexin (Cx50 or Gja8), subunits of lens gap junction channels, cause a variety of cataracts via unknown mechanisms. We identified a dominant cataractous mouse line (L1), caused by a missense ␣8 connexin mutation that resulted in the expression of ␣8-S50P mutant proteins. Histology studies showed that primary lens fiber cells failed to fully elongate in heterozygous ␣8 S50P/+ embryonic lenses, but not in homozygous ␣8, ␣8 -/-and ␣3 -/-␣8 -/-mutant embryonic lenses. We hypothesized that ␣8-S50P mutant subunits interacted with wild-type ␣3 or ␣8, or with both subunits to affect fiber cell formation. We found that the combination of mutant ␣8-S50P and wild-type ␣8 subunits specifically inhibited the elongation of primary fiber cells, while the combination of ␣8-S50P and wild-type ␣3 subunits disrupted the formation of secondary fiber cells. Thus, this work provides the first in vivo evidence that distinct mechanisms, modulated by diverse gap junctions, control the formation of primary and secondary fiber cells during lens development. This explains why and how different connexin mutations lead to a variety of cataracts. The principle of this explanation can also be applied to mutations of other connexin isoforms that cause different diseases in other organs.

This work demonstrates that different regions of alphaA-crystallin mediate distinct functions in vivo. These two mutant mouse lines provide useful animal models for further investigating the multiple roles of alphaA-crystallin in the lens.

. Knock-in of ␣3 connexin prevents severe cataracts caused by an ␣8 point mutation. J. Cell Sci. 119, 2138-2144.We apologise for an error that occurred in the heading of Table 2, which wrongly stated 'heteromeric' instead of 'homotypic' and 'heterotypic' instead of 'heteromeric'. This error appeared in both the print and the online versions of this article. The correct version is shown below. G jmin represents the minimum conductance value, V 0 indicates the transjunctional voltage value midway through the G j decline, and A denotes the cooperativity constant, reflecting the number of charges moving through the transjunctional field. Signs + and -for V j indicate transjunctional potential polarity.