Cargando…

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...

Descripción completa

Detalles Bibliográficos
Autores principales: Persiconi, Irene, Cosmi, Francesca, Guadagno, Noemi Antonella, Lupo, Giuseppe, De Stefano, Maria Egle
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Frontiers Media S.A. 2020
Materias:
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
_version_ 1783581480123891712
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
work_keys_str_mv AT persiconiirene dystrophinisrequiredforthepropertiminginretinalhistogenesisathoroughinvestigationonthemdxmousemodelofduchennemusculardystrophy
AT cosmifrancesca dystrophinisrequiredforthepropertiminginretinalhistogenesisathoroughinvestigationonthemdxmousemodelofduchennemusculardystrophy
AT guadagnonoemiantonella dystrophinisrequiredforthepropertiminginretinalhistogenesisathoroughinvestigationonthemdxmousemodelofduchennemusculardystrophy
AT lupogiuseppe dystrophinisrequiredforthepropertiminginretinalhistogenesisathoroughinvestigationonthemdxmousemodelofduchennemusculardystrophy
AT destefanomariaegle dystrophinisrequiredforthepropertiminginretinalhistogenesisathoroughinvestigationonthemdxmousemodelofduchennemusculardystrophy