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Early expression of the gene for interphotoreceptor retinol-binding protein during photoreceptor differentiation suggests a critical role for the interphotoreceptor matrix in retinal development.

ABSTRACT: Interphotoreceptor retinol-binding protein (IRBP), the major protein component of the subretinal space, is in a strategic position to mediate cellular interactions between the retinal pigmented epithelium (RPE) and the neural retina. While IRBP appears to be involved in vitamin A transport during the visual cycle in the adult, the role of this protein during eye development has not been determined. As a first step to understanding the role of IRBP during retinal development, we have studied the expression of the mRNA for this glycolipoprotein during photoreceptor differentiation in the rat. A rat neural retina cDNA library was prepared from which an IRBP clone was isolated. The clone contains an open reading frame followed by a 3' noncoding sequence ending in 10 adenosine residues. The coding region has an identity of 83.9 and 82.5% with the nucleotide sequence of human and bovine IRBP, respectively. Rats (Sprague-Dawley, Wistar, and Royal College of Surgeon pink-eyed controls) have a 6.4 and a 5.2-kb mRNA for IRBP which are present in a 1:4 ratio and thus are the only vertebrate known to definitely have more than one major form of the IRBP message. Genomic Southern blots are consistent with the hypothesis that there is only one allele of the IRBP gene, suggesting that the two forms are produced by alternative processing of the mRNA. To generate an antisense RNA probe for use in molecular titration assays and Northern blots, an Eco RI-Bam HI fragment from the coding region was subcloned in between flanking Sp6 and T7 promoters. Total RNA was prepared from undissected rat globes from postnatal days p0-p22. The expression of the mRNA for IRBP was studied by Northern blots and the level of the transcripts determined by solution hybridization assays. Approximately 10(5) IRBP mRNA transcripts/micrograms total eye RNA are present at birth. This increases to a final level of 3.1 X 10(6) transcripts/micrograms total RNA by p9. The one-half maximal level of the mRNA occurs at p4.2 which is 2 wk before the one-half maximal level of IRBP is reached in the subretinal space (Gonzalez-Fernandez, F., R. A. Landers, P. A. Glazebrook, S.-L. Fong, G. I. Liou, D. M. K. Lam, and C. D. B. Bridges. 1984. J. Cell Biol. 99:2092-2098). The expression of the mRNA for IRBP reflects the developmental emergence of the interphotoreceptor matrix as an important structure within the retina.(ABSTRACT TRUNCATED AT 400 WORDS)

SUBMITTER: Gonzalez-Fernandez F

PROVIDER: S-EPMC2116398 | biostudies-other | 1990 Dec

REPOSITORIES: biostudies-other

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Project description:Photoreceptor neurons are surrounded by an extracellular matrix, called the interphotoreceptor matrix (IPM). Activities crucial to vision occur within the IPM, including trafficking of nutrients and metabolites, retinal attachment, and interactions needed for normal outer segment phagocytosis. The IPM includes the following two unique proteoglycans: IPM proteoglycan 1 (IMPG1) and IMPG2. Patients with mutations in IMPG1/IMPG2 develop visual deficits with subretinal material accumulation, highlighting the critical role of the IPM in vision. To determine the role of these proteoglycans in retinal physiology and the pathologic mechanisms that lead to vision loss, we generated mouse models lacking IMPG1/IMPG2. In normal retina, IMPG1 and IMPG2 occupy distinct IPM compartments, represent the main source of chondroitin sulfate and are fundamental for the constitution of the cone-specific glycocalyx stained by the PNA (peanut agglutinin) lectin marker. No evident morphologic or functional deficits were found in mice lacking IMPG1. In the absence of IMPG2, IMPG1 abnormally accumulated at the subretinal space need, likely leading to the formation of subretinal lesions and reduced visual function. Interestingly, mice lacking both IMPG1 and IMPG2, regardless of sex, showed normal retinal structure and function, demonstrating that the aberrant IMPG1 distribution is the main cause of the visual alterations observed in the absence of IMPG2. In conclusion, our results show the dependence of secreted proteoglycans such as IMPG1 on the extracellular environment to properly integrate into the matrix, demonstrate the role of IMPG2 in shaping the IPM, and shed light on the potential mechanisms leading to the development of subretinal lesions and vision loss.SIGNIFICANCE STATEMENT The photoreceptors are specialized neurons that drive phototransduction in the mammalian retina. These cells are organized and surrounded by an extracellular matrix, the interphotoreceptor matrix (IPM). Mutations in IPM proteoglycans are associated with blindness in humans. Our studies show that two specific proteoglycans of the IPM, IPM proteoglycan 1 (IMPG1) and IMPG2, form a dynamic structure with distinct localization and dependency. When IMPG2 is absent, IMPG1 cannot integrate into the IPM, leading to abnormal proteoglycan accumulation and visual deficits. This work adds a new layer of understanding to IPM physiology and describes the pathologic events following deficits in proteoglycans, providing novel possibilities for visual restoration in patients with IMPG-related pathologies.

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Early expression of the gene for interphotoreceptor retinol-binding protein during photoreceptor differentiation suggests a critical role for the interphotoreceptor matrix in retinal development.

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