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Dystrophin Is Required for the Proper Timing in Retinal Histogenesis: A Thorough Investigation on the mdx Mouse Model of Duchenne Muscular Dystrophy
Duchenne muscular dystrophy (DMD) is a lethal X-linked muscular disease caused by defective expression of the cytoskeletal protein dystrophin (Dp427). Selected autonomic and central neurons, including retinal neurons, express Dp427 and/or dystrophin shorter isoforms. Because of this, DMD patients ma...
Autores principales: | , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
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Frontiers Media S.A.
2020
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Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7487415/ https://www.ncbi.nlm.nih.gov/pubmed/32982660 http://dx.doi.org/10.3389/fnins.2020.00760 |
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author | Persiconi, Irene Cosmi, Francesca Guadagno, Noemi Antonella Lupo, Giuseppe De Stefano, Maria Egle |
author_facet | Persiconi, Irene Cosmi, Francesca Guadagno, Noemi Antonella Lupo, Giuseppe De Stefano, Maria Egle |
author_sort | Persiconi, Irene |
collection | PubMed |
description | Duchenne muscular dystrophy (DMD) is a lethal X-linked muscular disease caused by defective expression of the cytoskeletal protein dystrophin (Dp427). Selected autonomic and central neurons, including retinal neurons, express Dp427 and/or dystrophin shorter isoforms. Because of this, DMD patients may also experience different forms of cognitive impairment, neurological and autonomic disorders, and specific visual defects. DMD-related damages to the nervous system are established during development, suggesting a role for all dystrophin isoforms in neural circuit development and differentiation; however, to date, their function in retinogenesis has never been investigated. In this large-scale study, we analyzed whether the lack of Dp427 affects late retinogenesis in the mdx mouse, the most well studied animal model of DMD. Retinal gene expression and layer maturation, as well as neural cell proliferation, apoptosis, and differentiation, were evaluated in E18 and/or P0, P5, P10, and adult mice. In mdx mice, expression of Capn3, Id3 (E18-P5), and Dtnb (P5) genes, encoding proteins involved in different aspects of retina development and synaptogenesis (e.g., Calpain 3, DNA-binding protein inhibitor-3, and β-dystrobrevin, respectively), was transiently reduced compared to age-matched wild type mice. Concomitantly, a difference in the time required for the retinal ganglion cell layer to reach appropriate thickness was observed (P0–P5). Immunolabeling for specific cell markers also evidenced a significant dysregulation in the number of GABAergic amacrine cells (P5–P10), a transient decrease in the area immunopositive for the Vesicular Glutamate Transporter 1 (VGluT1) during ribbon synapse maturation (P10) and a reduction in the number of calretinin(+) retinal ganglion cells (RGCs) (adults). Finally, the number of proliferating retinal progenitor cells (P5–P10) and apoptotic cells (P10) was reduced. These results support the hypothesis of a role for Dp427 during late retinogenesis different from those proposed in consolidated neural circuits. In particular, Dp427 may be involved in shaping specific steps of retina differentiation. Notably, although most of the above described quantitative alterations recover over time, the number of calretinin(+) RGCs is reduced only in the mature retina. This suggests that alterations subtler than the timing of retinal maturation may occur, a hypothesis that demands further in-depth functional studies. |
format | Online Article Text |
id | pubmed-7487415 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2020 |
publisher | Frontiers Media S.A. |
record_format | MEDLINE/PubMed |
spelling | pubmed-74874152020-09-25 Dystrophin Is Required for the Proper Timing in Retinal Histogenesis: A Thorough Investigation on the mdx Mouse Model of Duchenne Muscular Dystrophy Persiconi, Irene Cosmi, Francesca Guadagno, Noemi Antonella Lupo, Giuseppe De Stefano, Maria Egle Front Neurosci Neuroscience Duchenne muscular dystrophy (DMD) is a lethal X-linked muscular disease caused by defective expression of the cytoskeletal protein dystrophin (Dp427). Selected autonomic and central neurons, including retinal neurons, express Dp427 and/or dystrophin shorter isoforms. Because of this, DMD patients may also experience different forms of cognitive impairment, neurological and autonomic disorders, and specific visual defects. DMD-related damages to the nervous system are established during development, suggesting a role for all dystrophin isoforms in neural circuit development and differentiation; however, to date, their function in retinogenesis has never been investigated. In this large-scale study, we analyzed whether the lack of Dp427 affects late retinogenesis in the mdx mouse, the most well studied animal model of DMD. Retinal gene expression and layer maturation, as well as neural cell proliferation, apoptosis, and differentiation, were evaluated in E18 and/or P0, P5, P10, and adult mice. In mdx mice, expression of Capn3, Id3 (E18-P5), and Dtnb (P5) genes, encoding proteins involved in different aspects of retina development and synaptogenesis (e.g., Calpain 3, DNA-binding protein inhibitor-3, and β-dystrobrevin, respectively), was transiently reduced compared to age-matched wild type mice. Concomitantly, a difference in the time required for the retinal ganglion cell layer to reach appropriate thickness was observed (P0–P5). Immunolabeling for specific cell markers also evidenced a significant dysregulation in the number of GABAergic amacrine cells (P5–P10), a transient decrease in the area immunopositive for the Vesicular Glutamate Transporter 1 (VGluT1) during ribbon synapse maturation (P10) and a reduction in the number of calretinin(+) retinal ganglion cells (RGCs) (adults). Finally, the number of proliferating retinal progenitor cells (P5–P10) and apoptotic cells (P10) was reduced. These results support the hypothesis of a role for Dp427 during late retinogenesis different from those proposed in consolidated neural circuits. In particular, Dp427 may be involved in shaping specific steps of retina differentiation. Notably, although most of the above described quantitative alterations recover over time, the number of calretinin(+) RGCs is reduced only in the mature retina. This suggests that alterations subtler than the timing of retinal maturation may occur, a hypothesis that demands further in-depth functional studies. Frontiers Media S.A. 2020-08-31 /pmc/articles/PMC7487415/ /pubmed/32982660 http://dx.doi.org/10.3389/fnins.2020.00760 Text en Copyright © 2020 Persiconi, Cosmi, Guadagno, Lupo and De Stefano. http://creativecommons.org/licenses/by/4.0/ This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms. |
spellingShingle | Neuroscience Persiconi, Irene Cosmi, Francesca Guadagno, Noemi Antonella Lupo, Giuseppe De Stefano, Maria Egle Dystrophin Is Required for the Proper Timing in Retinal Histogenesis: A Thorough Investigation on the mdx Mouse Model of Duchenne Muscular Dystrophy |
title | Dystrophin Is Required for the Proper Timing in Retinal Histogenesis: A Thorough Investigation on the mdx Mouse Model of Duchenne Muscular Dystrophy |
title_full | Dystrophin Is Required for the Proper Timing in Retinal Histogenesis: A Thorough Investigation on the mdx Mouse Model of Duchenne Muscular Dystrophy |
title_fullStr | Dystrophin Is Required for the Proper Timing in Retinal Histogenesis: A Thorough Investigation on the mdx Mouse Model of Duchenne Muscular Dystrophy |
title_full_unstemmed | Dystrophin Is Required for the Proper Timing in Retinal Histogenesis: A Thorough Investigation on the mdx Mouse Model of Duchenne Muscular Dystrophy |
title_short | Dystrophin Is Required for the Proper Timing in Retinal Histogenesis: A Thorough Investigation on the mdx Mouse Model of Duchenne Muscular Dystrophy |
title_sort | dystrophin is required for the proper timing in retinal histogenesis: a thorough investigation on the mdx mouse model of duchenne muscular dystrophy |
topic | Neuroscience |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7487415/ https://www.ncbi.nlm.nih.gov/pubmed/32982660 http://dx.doi.org/10.3389/fnins.2020.00760 |
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