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Photoreceptor degeneration in microphthalmia (Mitf) mice: partial rescue by pigment epithelium-derived factor.

ABSTRACT: Dysfunction and loss of the retinal pigment epithelium (RPE) are hallmarks of retinal degeneration, but the underlying pathogenetic processes are only partially understood. Using mice with a null mutation in the transcription factor gene Mitf, in which RPE deficiencies are associated with retinal degeneration, we evaluated the role of trophic factors secreted by the RPE in retinal homeostasis. In such mice, the thickness of the outer nuclear layer (ONL) is as in wild type up to postnatal day 10, but then is progressively reduced, associated with a marked increase in the number of apoptotic cells and a decline in staining for rhodopsin. We show that retinal degeneration and decrease in rhodopsin staining can be prevented partially in three different ways: first, by recombining mutant-derived postnatal retina with postnatal wild-type RPE in tissue explant cultures; second, by adding to cultured mutant retina the trophic factor pigment epithelium-derived factor (PEDF; also known as SERPINF1), which is normally produced in RPE under the control of Mitf; and third, by treating the eyes of Mitf mutant mice in vivo with drops containing a bioactive PEDF 17-mer peptide. This latter treatment also led to marked increases in a number of rod and cone genes. The results indicate that RPE-derived trophic factors, in particular PEDF, are instrumental in retinal homeostasis, and suggest that PEDF or its bioactive fragments may have therapeutic potential in RPE deficiency-associated retinal degeneration.

SUBMITTER: Chen Y

PROVIDER: S-EPMC6361154 | biostudies-literature | 2019 Jan

REPOSITORIES: biostudies-literature

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Photoreceptor degeneration in microphthalmia (<i>Mitf</i>) mice: partial rescue by pigment epithelium-derived factor.

Chen Yu Y Yang Juan J Geng Huiqin H Li Liping L Li Jinyang J Cheng Bing B Ma Xiaoyin X Li Huirong H Hou Ling L

Disease models & mechanisms 20190111 1

Dysfunction and loss of the retinal pigment epithelium (RPE) are hallmarks of retinal degeneration, but the underlying pathogenetic processes are only partially understood. Using mice with a null mutation in the transcription factor gene <i>Mitf</i>, in which RPE deficiencies are associated with retinal degeneration, we evaluated the role of trophic factors secreted by the RPE in retinal homeostasis. In such mice, the thickness of the outer nuclear layer (ONL) is as in wild type up to postnatal ...[more]

PMID: 30651300

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Project description:Microphthalmia-associated transcription factor (Mitf) is expressed in neural crest cell-derived melanocytes, and in the retinal pigment epithelium (RPE) during ocular development. Mutations in Mitf are associated with auditory/visual/pigmentary syndromes in humans. Mitf(mi/mi) mouse mutants lack pigmentation, and are microphthalmic, while Mitf(vit/vit) mouse mutants display abnormal RPE pigmentation, and progressive retinal degeneration. Microarray analysis was used to identify novel downstream gene targets/pathways in the RPE that are altered by mutations in the transcription factor Mitf. Using the Affymetrix platform, gene expression profiles were generated using the eyes of E13.5 mouse fetuses that were wildtype, heterozygous, or homozygous for the Mitf(mi) mutation. In a separate experiment, eyes from E13.5 mouse fetuses homozygous for the Mitf(vit) mutation were compared to eyes from the C57BL/6 control background strain. Statistical analyses were performed using robust multiarray average, mixed-effects ANOVA and random-variance t-tests. Altered expression of genes involved in pigment formation, melanosome biogenesis/transport, and redox homeostasis were observed. Twelve genes were commonly mis-regulated in the eyes of both Mitf mutants: 10 of these genes were downregulated in both mutants relative to controls, while 2 of the genes (Nramp1 (Slc11a1) and epoxide hydrolase) were downregulated in Mitf(mi/mi) mutants, and conversely, upregulated in Mitf(vit/vit) mutants. Quantitative RT-PCR and immunohistochemistry were used to confirm altered gene/protein expression. RPE expression of the Fe(+2) iron transporter Nramp1 (Slc11a1) has not previously been reported. Fe(+2) is an important co-factor utilized by the iron-dependent isomerohydrolase RPE65 in the retinoid visual cycle. However, excess accumulation of Fe(+2) in the RPE has recently been associated with oxidative damage and age-related macular degeneration. Abnormal pigmentation and increased activity of Slc11a1 in the RPE of Mitf(vit) mice may contribute to the pathology and progressive retinal degeneration observed in these mutants.

Dataset Information

Photoreceptor degeneration in microphthalmia (Mitf) mice: partial rescue by pigment epithelium-derived factor.

Publications

Photoreceptor degeneration in microphthalmia (<i>Mitf</i>) mice: partial rescue by pigment epithelium-derived factor.

Similar Datasets

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