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Gene Profiling of Postnatal Mfrp(rd6) Mutant Eyes Reveals Differential Accumulation of Prss56, Visual Cycle and Phototransduction mRNAs

Mutations in the membrane frizzled-related protein (MFRP/Mfrp) gene, specifically expressed in the retinal pigment epithelium (RPE) and ciliary body, cause nanophthalmia or posterior microphthalmia with retinitis pigmentosa in humans, and photoreceptor degeneration in mice. To better understand MFRP...

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Autores principales: Soundararajan, Ramani, Won, Jungyeon, Stearns, Timothy M., Charette, Jeremy R., Hicks, Wanda L., Collin, Gayle B., Naggert, Jürgen K., Krebs, Mark P., Nishina, Patsy M.
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Public Library of Science 2014
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4214712/
https://www.ncbi.nlm.nih.gov/pubmed/25357075
http://dx.doi.org/10.1371/journal.pone.0110299
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author Soundararajan, Ramani
Won, Jungyeon
Stearns, Timothy M.
Charette, Jeremy R.
Hicks, Wanda L.
Collin, Gayle B.
Naggert, Jürgen K.
Krebs, Mark P.
Nishina, Patsy M.
author_facet Soundararajan, Ramani
Won, Jungyeon
Stearns, Timothy M.
Charette, Jeremy R.
Hicks, Wanda L.
Collin, Gayle B.
Naggert, Jürgen K.
Krebs, Mark P.
Nishina, Patsy M.
author_sort Soundararajan, Ramani
collection PubMed
description Mutations in the membrane frizzled-related protein (MFRP/Mfrp) gene, specifically expressed in the retinal pigment epithelium (RPE) and ciliary body, cause nanophthalmia or posterior microphthalmia with retinitis pigmentosa in humans, and photoreceptor degeneration in mice. To better understand MFRP function, microarray analysis was performed on eyes of homozygous Mfrp(rd6) and C57BL/6J mice at postnatal days (P) 0 and P14, prior to photoreceptor loss. Data analysis revealed no changes at P0 but significant differences in RPE and retina-specific transcripts at P14, suggesting a postnatal influence of the Mfrp(rd6) allele. A subset of these transcripts was validated by quantitative real-time PCR (qRT-PCR). In Mfrp(rd6) eyes, a significant 1.5- to 2.0-fold decrease was observed among transcripts of genes linked to retinal degeneration, including those involved in visual cycle (Rpe65, Lrat, Rgr), phototransduction (Pde6a, Guca1b, Rgs9), and photoreceptor disc morphogenesis (Rpgrip1 and Fscn2). Levels of RPE65 were significantly decreased by 2.0-fold. Transcripts of Prss56, a gene associated with angle-closure glaucoma, posterior microphthalmia and myopia, were increased in Mfrp(rd6) eyes by 17-fold. Validation by qRT-PCR indicated a 3.5-, 14- and 70-fold accumulation of Prss56 transcripts relative to controls at P7, P14 and P21, respectively. This trend was not observed in other RPE or photoreceptor mutant mouse models with similar disease progression, suggesting that Prss56 upregulation is a specific attribute of the disruption of Mfrp. Prss56 and Glul in situ hybridization directly identified Müller glia in the inner nuclear layer as the cell type expressing Prss56. In summary, the Mfrp(rd6) allele causes significant postnatal changes in transcript and protein levels in the retina and RPE. The link between Mfrp deficiency and Prss56 up-regulation, together with the genetic association of human MFRP or PRSS56 variants and ocular size, raises the possibility that these genes are part of a regulatory network influencing postnatal posterior eye development.
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spelling pubmed-42147122014-11-05 Gene Profiling of Postnatal Mfrp(rd6) Mutant Eyes Reveals Differential Accumulation of Prss56, Visual Cycle and Phototransduction mRNAs Soundararajan, Ramani Won, Jungyeon Stearns, Timothy M. Charette, Jeremy R. Hicks, Wanda L. Collin, Gayle B. Naggert, Jürgen K. Krebs, Mark P. Nishina, Patsy M. PLoS One Research Article Mutations in the membrane frizzled-related protein (MFRP/Mfrp) gene, specifically expressed in the retinal pigment epithelium (RPE) and ciliary body, cause nanophthalmia or posterior microphthalmia with retinitis pigmentosa in humans, and photoreceptor degeneration in mice. To better understand MFRP function, microarray analysis was performed on eyes of homozygous Mfrp(rd6) and C57BL/6J mice at postnatal days (P) 0 and P14, prior to photoreceptor loss. Data analysis revealed no changes at P0 but significant differences in RPE and retina-specific transcripts at P14, suggesting a postnatal influence of the Mfrp(rd6) allele. A subset of these transcripts was validated by quantitative real-time PCR (qRT-PCR). In Mfrp(rd6) eyes, a significant 1.5- to 2.0-fold decrease was observed among transcripts of genes linked to retinal degeneration, including those involved in visual cycle (Rpe65, Lrat, Rgr), phototransduction (Pde6a, Guca1b, Rgs9), and photoreceptor disc morphogenesis (Rpgrip1 and Fscn2). Levels of RPE65 were significantly decreased by 2.0-fold. Transcripts of Prss56, a gene associated with angle-closure glaucoma, posterior microphthalmia and myopia, were increased in Mfrp(rd6) eyes by 17-fold. Validation by qRT-PCR indicated a 3.5-, 14- and 70-fold accumulation of Prss56 transcripts relative to controls at P7, P14 and P21, respectively. This trend was not observed in other RPE or photoreceptor mutant mouse models with similar disease progression, suggesting that Prss56 upregulation is a specific attribute of the disruption of Mfrp. Prss56 and Glul in situ hybridization directly identified Müller glia in the inner nuclear layer as the cell type expressing Prss56. In summary, the Mfrp(rd6) allele causes significant postnatal changes in transcript and protein levels in the retina and RPE. The link between Mfrp deficiency and Prss56 up-regulation, together with the genetic association of human MFRP or PRSS56 variants and ocular size, raises the possibility that these genes are part of a regulatory network influencing postnatal posterior eye development. Public Library of Science 2014-10-30 /pmc/articles/PMC4214712/ /pubmed/25357075 http://dx.doi.org/10.1371/journal.pone.0110299 Text en © 2014 Soundararajan et al http://creativecommons.org/licenses/by/4.0/ This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are properly credited.
spellingShingle Research Article
Soundararajan, Ramani
Won, Jungyeon
Stearns, Timothy M.
Charette, Jeremy R.
Hicks, Wanda L.
Collin, Gayle B.
Naggert, Jürgen K.
Krebs, Mark P.
Nishina, Patsy M.
Gene Profiling of Postnatal Mfrp(rd6) Mutant Eyes Reveals Differential Accumulation of Prss56, Visual Cycle and Phototransduction mRNAs
title Gene Profiling of Postnatal Mfrp(rd6) Mutant Eyes Reveals Differential Accumulation of Prss56, Visual Cycle and Phototransduction mRNAs
title_full Gene Profiling of Postnatal Mfrp(rd6) Mutant Eyes Reveals Differential Accumulation of Prss56, Visual Cycle and Phototransduction mRNAs
title_fullStr Gene Profiling of Postnatal Mfrp(rd6) Mutant Eyes Reveals Differential Accumulation of Prss56, Visual Cycle and Phototransduction mRNAs
title_full_unstemmed Gene Profiling of Postnatal Mfrp(rd6) Mutant Eyes Reveals Differential Accumulation of Prss56, Visual Cycle and Phototransduction mRNAs
title_short Gene Profiling of Postnatal Mfrp(rd6) Mutant Eyes Reveals Differential Accumulation of Prss56, Visual Cycle and Phototransduction mRNAs
title_sort gene profiling of postnatal mfrp(rd6) mutant eyes reveals differential accumulation of prss56, visual cycle and phototransduction mrnas
topic Research Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4214712/
https://www.ncbi.nlm.nih.gov/pubmed/25357075
http://dx.doi.org/10.1371/journal.pone.0110299
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