M.Morita and O.Ohneda contributed equally to this workAn HLF (HIF-1a-like factor)/HIF-2a-knockout mouse is embryonic lethal, preventing investigation of HLF function in adult mice. To investigate the role of HLF in adult pathological angiogenesis, we generated HLF-knockdown (HLF kd/kd ) mice by inserting a neomycin gene sandwiched between two loxP sequences into exon 1 of the HLF gene. HLF kd/kd mice expressing 80±20% reduction, depending on the tissue, in wildtype HLF mRNA were fertile and apparently normal. Hyperoxia±normoxia treatment, used as a murine model of retinopathy of prematurity (ROP), induced neovascularization in wild-type mice, but not in HLF kd/kd mice, whereas prolonged normoxia following hyperoxic treatment caused degeneration of retinal neural layers in HLF kd/kd mice due to poor vascularization. Cre-mediated removal of the inserted gene recovered normal HLF expression and retinal neovascularization in HLF kd/kd mice. Expression levels of various angiogenic factors revealed that only erythropoietin (Epo) gene expression was signi®cantly affected, in parallel with HLF expression. Together with the results from intraperitoneal injection of Epo into HLF kd/kd mouse, this suggests that Epo is one of the target genes of HLF responsible for experimental ROP.

Oguchi disease is a rare autosomal recessive form of congenital stationary night blindness with all other visual functions, including visual acuity, visual field, and colour vision being usually normal. A typical clinical feature of the disorder is a golden or gray-white discolouration of the fundus which disappears in the dark-adapted state and reappears shortly after the onset of light ('Mizuo phenomenon'; Fig. 1). The course of dark adaptation of rod photoreceptors is extremely retarded in Oguchi disease while that of cones appears to proceed normally. The locus for Oguchi disease was recently mapped between D2S172 and D2S345 on distal chromosome 2q by linkage analysis. Interestingly, the gene for arrestin, an intrinsic rod photoreceptor protein implicated in the recovery phase of light transduction, also maps to this region of chromosome 2q (refs 6, 7). Here we report that in five out of six unrelated Japanese patients with Oguchi disease, we have identified a homozygous deletion of nucleotide 1147 (1147delA) in codon 309 of the arrestin gene, predicting a shift in the reading frame and a premature termination of translation which may result in 'functional null alleles.'

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Channelrhodopsin-2 (ChR2), one of the archea-type rhodopsins from green algae, is a potentially useful optogenetic tool for restoring vision in patients with photoreceptor degeneration, such as retinitis pigmentosa. If the ChR2 gene is transferred to retinal ganglion cells (RGCs), which send visual information to the brain, the RGCs may be repurposed to act as photoreceptors. In this study, by using a transgenic rat expressing ChR2 specifically in the RGCs under the regulation of a Thy-1.2 promoter, we tested the possibility that direct photoactivation of RGCs could restore effective vision. Although the contrast sensitivities of the optomotor responses of transgenic rats were similar to those observed in the wild-type rats, they were enhanced for visual stimuli of low-spatial frequency after the degeneration of native photoreceptors. This result suggests that the visual signals derived from the ChR2-expressing RGCs were reinterpreted by the brain to form behavior-related vision.

No abstract