Alternative splicing of the APC gene in the neural retina and retinal pigment epithelium

Gregory I. Liou, Sara Samuel, Suraporn Matragoon, Kathleen H. Goss, Irma Santoro, Joanna Groden, Richard C. Hunt, Fei Wang, Sheldon S. Miller, Ruth B Caldwell, Anil K. Rustgi, Harinderjit Singh, Dennis M. Marcus

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Abstract

Purpose: Hypertrophy and hyperplasia of the retinal pigment epithelium (RPE) is associated with an inherited predisposition to human familial adenomatous polyposis coli, suggesting that expression of the adenomatous polyposis coli (APC) tumor suppressor may regulate RPE proliferation/differentiation. Distinctive APC isoforms exist in different cell types due to alternative splicing of the APC transcripts. We hypothesize that differences in expression patterns of APC protein isoforms are critical to RPE proliferation/differentiation. Methods: To investigate these relationships, APC gene expression was characterized in the retinas and RPE from fetal and adult human and mouse, and in the epiretinal membranes (ERM) from 5 patients with proliferative vitreoretinopathy (PVR). Expression patterns of alternative splice-forms of APC transcripts were evaluated by comparative quantitative RT-PCR. Exon 1 of APC encodes a heptad repeat that confers the ability of APC to homodimerize. APC protein isoforms containing or lacking this heptad were characterized by western blot analysis and immunohistochemistry. Results: Comparative quantitative RT-PCR demonstrated a predominant exon 1 containing, conventional APC splice-form in the early developing fetal RPE and retina, and in all the tested ERM samples from patients with PVR. This method also demonstrated an increased level of exon 1 lacking APC splice-form in the mature RPE and retina. Western blot analysis and immunofluorescence microscopy demonstrated the conventional APC only in the RPE, and the APC isoform without the first heptad repeat in both the retina and RPE. Immunofluorescence microscopy also demonstrated only the conventional APC in the ERM samples tested. Conclusions: These results suggest that alternative splicing of APC leads to differential APC expression with potentially unique functions. APC isoform without the first heptad repeat may play a role in cell cycle cessation in the adult retina and RPE, and the down regulation of this APC isoform may contribute to the potential of RPE to migrate and proliferate.

Original languageEnglish (US)
Pages (from-to)383-391
Number of pages9
JournalMolecular Vision
Volume10
StatePublished - Jun 14 2004

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APC Genes
Adenomatous Polyposis Coli
Retinal Pigment Epithelium
Alternative Splicing
Retina
Protein Isoforms
Epiretinal Membrane
Adenomatous Polyposis Coli Protein
Proliferative Vitreoretinopathy
Exons
Fluorescence Microscopy
Western Blotting
Polymerase Chain Reaction

ASJC Scopus subject areas

  • Ophthalmology

Cite this

Liou, G. I., Samuel, S., Matragoon, S., Goss, K. H., Santoro, I., Groden, J., ... Marcus, D. M. (2004). Alternative splicing of the APC gene in the neural retina and retinal pigment epithelium. Molecular Vision, 10, 383-391.

Alternative splicing of the APC gene in the neural retina and retinal pigment epithelium. / Liou, Gregory I.; Samuel, Sara; Matragoon, Suraporn; Goss, Kathleen H.; Santoro, Irma; Groden, Joanna; Hunt, Richard C.; Wang, Fei; Miller, Sheldon S.; Caldwell, Ruth B; Rustgi, Anil K.; Singh, Harinderjit; Marcus, Dennis M.

In: Molecular Vision, Vol. 10, 14.06.2004, p. 383-391.

Research output: Contribution to journalArticle

Liou, GI, Samuel, S, Matragoon, S, Goss, KH, Santoro, I, Groden, J, Hunt, RC, Wang, F, Miller, SS, Caldwell, RB, Rustgi, AK, Singh, H & Marcus, DM 2004, 'Alternative splicing of the APC gene in the neural retina and retinal pigment epithelium', Molecular Vision, vol. 10, pp. 383-391.
Liou GI, Samuel S, Matragoon S, Goss KH, Santoro I, Groden J et al. Alternative splicing of the APC gene in the neural retina and retinal pigment epithelium. Molecular Vision. 2004 Jun 14;10:383-391.
Liou, Gregory I. ; Samuel, Sara ; Matragoon, Suraporn ; Goss, Kathleen H. ; Santoro, Irma ; Groden, Joanna ; Hunt, Richard C. ; Wang, Fei ; Miller, Sheldon S. ; Caldwell, Ruth B ; Rustgi, Anil K. ; Singh, Harinderjit ; Marcus, Dennis M. / Alternative splicing of the APC gene in the neural retina and retinal pigment epithelium. In: Molecular Vision. 2004 ; Vol. 10. pp. 383-391.
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abstract = "Purpose: Hypertrophy and hyperplasia of the retinal pigment epithelium (RPE) is associated with an inherited predisposition to human familial adenomatous polyposis coli, suggesting that expression of the adenomatous polyposis coli (APC) tumor suppressor may regulate RPE proliferation/differentiation. Distinctive APC isoforms exist in different cell types due to alternative splicing of the APC transcripts. We hypothesize that differences in expression patterns of APC protein isoforms are critical to RPE proliferation/differentiation. Methods: To investigate these relationships, APC gene expression was characterized in the retinas and RPE from fetal and adult human and mouse, and in the epiretinal membranes (ERM) from 5 patients with proliferative vitreoretinopathy (PVR). Expression patterns of alternative splice-forms of APC transcripts were evaluated by comparative quantitative RT-PCR. Exon 1 of APC encodes a heptad repeat that confers the ability of APC to homodimerize. APC protein isoforms containing or lacking this heptad were characterized by western blot analysis and immunohistochemistry. Results: Comparative quantitative RT-PCR demonstrated a predominant exon 1 containing, conventional APC splice-form in the early developing fetal RPE and retina, and in all the tested ERM samples from patients with PVR. This method also demonstrated an increased level of exon 1 lacking APC splice-form in the mature RPE and retina. Western blot analysis and immunofluorescence microscopy demonstrated the conventional APC only in the RPE, and the APC isoform without the first heptad repeat in both the retina and RPE. Immunofluorescence microscopy also demonstrated only the conventional APC in the ERM samples tested. Conclusions: These results suggest that alternative splicing of APC leads to differential APC expression with potentially unique functions. APC isoform without the first heptad repeat may play a role in cell cycle cessation in the adult retina and RPE, and the down regulation of this APC isoform may contribute to the potential of RPE to migrate and proliferate.",
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AU - Samuel, Sara

AU - Matragoon, Suraporn

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AU - Santoro, Irma

AU - Groden, Joanna

AU - Hunt, Richard C.

AU - Wang, Fei

AU - Miller, Sheldon S.

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AU - Rustgi, Anil K.

AU - Singh, Harinderjit

AU - Marcus, Dennis M.

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N2 - Purpose: Hypertrophy and hyperplasia of the retinal pigment epithelium (RPE) is associated with an inherited predisposition to human familial adenomatous polyposis coli, suggesting that expression of the adenomatous polyposis coli (APC) tumor suppressor may regulate RPE proliferation/differentiation. Distinctive APC isoforms exist in different cell types due to alternative splicing of the APC transcripts. We hypothesize that differences in expression patterns of APC protein isoforms are critical to RPE proliferation/differentiation. Methods: To investigate these relationships, APC gene expression was characterized in the retinas and RPE from fetal and adult human and mouse, and in the epiretinal membranes (ERM) from 5 patients with proliferative vitreoretinopathy (PVR). Expression patterns of alternative splice-forms of APC transcripts were evaluated by comparative quantitative RT-PCR. Exon 1 of APC encodes a heptad repeat that confers the ability of APC to homodimerize. APC protein isoforms containing or lacking this heptad were characterized by western blot analysis and immunohistochemistry. Results: Comparative quantitative RT-PCR demonstrated a predominant exon 1 containing, conventional APC splice-form in the early developing fetal RPE and retina, and in all the tested ERM samples from patients with PVR. This method also demonstrated an increased level of exon 1 lacking APC splice-form in the mature RPE and retina. Western blot analysis and immunofluorescence microscopy demonstrated the conventional APC only in the RPE, and the APC isoform without the first heptad repeat in both the retina and RPE. Immunofluorescence microscopy also demonstrated only the conventional APC in the ERM samples tested. Conclusions: These results suggest that alternative splicing of APC leads to differential APC expression with potentially unique functions. APC isoform without the first heptad repeat may play a role in cell cycle cessation in the adult retina and RPE, and the down regulation of this APC isoform may contribute to the potential of RPE to migrate and proliferate.

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