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Analysis of Drosophila and mouse mutants reveals that Peroxidasin is required for tissue mechanics and full viability

Basement membranes are thin strong sheets of extracellular matrix. They provide mechanical and biochemical support to epithelia, muscles, nerves, and blood vessels, among other tissues. The mechanical properties of basement membranes are conferred in part by Collagen IV (Col4), an abundant protein o...

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Autores principales: Peebles, K. Elkie, LaFever, Kimberly S., Page-McCaw, Patrick S., Colon, Selene, Wang, Dan, Stricker, Aubrie M., Ferrell, Nicholas, Bhave, Gautam, Page-McCaw, Andrea
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Cold Spring Harbor Laboratory 2023
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10370120/
https://www.ncbi.nlm.nih.gov/pubmed/37503104
http://dx.doi.org/10.1101/2023.07.19.549730
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author Peebles, K. Elkie
LaFever, Kimberly S.
Page-McCaw, Patrick S.
Colon, Selene
Wang, Dan
Stricker, Aubrie M.
Ferrell, Nicholas
Bhave, Gautam
Page-McCaw, Andrea
author_facet Peebles, K. Elkie
LaFever, Kimberly S.
Page-McCaw, Patrick S.
Colon, Selene
Wang, Dan
Stricker, Aubrie M.
Ferrell, Nicholas
Bhave, Gautam
Page-McCaw, Andrea
author_sort Peebles, K. Elkie
collection PubMed
description Basement membranes are thin strong sheets of extracellular matrix. They provide mechanical and biochemical support to epithelia, muscles, nerves, and blood vessels, among other tissues. The mechanical properties of basement membranes are conferred in part by Collagen IV (Col4), an abundant protein of basement membrane that forms an extensive two-dimensional network through head-to-head and tail-to-tail interactions. After the Col4 network is assembled into a basement membrane, it is crosslinked by the matrix-resident enzyme Peroxidasin to form a large covalent polymer. Peroxidasin and Col4 crosslinking are highly conserved, indicating they are essential, but homozygous mutant mice have mild phenotypes. To explore the role of Peroxidasin, we analyzed mutants in Drosophila, including a newly generated catalytic null, and found that homozygotes were mostly lethal with 13% viable escapers. A Mendelian analysis of mouse mutants shows a similar pattern, with homozygotes displaying ~50% lethality and ~50% escapers. Despite the strong mutations, the homozygous escapers had low but detectable levels of Col4 crosslinking, indicating that inefficient alternative mechanisms exist and that are probably responsible for the viable escapers. Further, fly mutants have phenotypes consistent with a decrease in stiffness. Interestingly, we found that even after adult basement membranes are assembled and crosslinked, Peroxidasin is still required to maintain stiffness. These results suggest that Peroxidasin crosslinking may be more important than previously appreciated.
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spelling pubmed-103701202023-07-27 Analysis of Drosophila and mouse mutants reveals that Peroxidasin is required for tissue mechanics and full viability Peebles, K. Elkie LaFever, Kimberly S. Page-McCaw, Patrick S. Colon, Selene Wang, Dan Stricker, Aubrie M. Ferrell, Nicholas Bhave, Gautam Page-McCaw, Andrea bioRxiv Article Basement membranes are thin strong sheets of extracellular matrix. They provide mechanical and biochemical support to epithelia, muscles, nerves, and blood vessels, among other tissues. The mechanical properties of basement membranes are conferred in part by Collagen IV (Col4), an abundant protein of basement membrane that forms an extensive two-dimensional network through head-to-head and tail-to-tail interactions. After the Col4 network is assembled into a basement membrane, it is crosslinked by the matrix-resident enzyme Peroxidasin to form a large covalent polymer. Peroxidasin and Col4 crosslinking are highly conserved, indicating they are essential, but homozygous mutant mice have mild phenotypes. To explore the role of Peroxidasin, we analyzed mutants in Drosophila, including a newly generated catalytic null, and found that homozygotes were mostly lethal with 13% viable escapers. A Mendelian analysis of mouse mutants shows a similar pattern, with homozygotes displaying ~50% lethality and ~50% escapers. Despite the strong mutations, the homozygous escapers had low but detectable levels of Col4 crosslinking, indicating that inefficient alternative mechanisms exist and that are probably responsible for the viable escapers. Further, fly mutants have phenotypes consistent with a decrease in stiffness. Interestingly, we found that even after adult basement membranes are assembled and crosslinked, Peroxidasin is still required to maintain stiffness. These results suggest that Peroxidasin crosslinking may be more important than previously appreciated. Cold Spring Harbor Laboratory 2023-07-19 /pmc/articles/PMC10370120/ /pubmed/37503104 http://dx.doi.org/10.1101/2023.07.19.549730 Text en https://creativecommons.org/licenses/by-nc-nd/4.0/This work is licensed under a Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 International License (https://creativecommons.org/licenses/by-nc-nd/4.0/) , which allows reusers to copy and distribute the material in any medium or format in unadapted form only, for noncommercial purposes only, and only so long as attribution is given to the creator.
spellingShingle Article
Peebles, K. Elkie
LaFever, Kimberly S.
Page-McCaw, Patrick S.
Colon, Selene
Wang, Dan
Stricker, Aubrie M.
Ferrell, Nicholas
Bhave, Gautam
Page-McCaw, Andrea
Analysis of Drosophila and mouse mutants reveals that Peroxidasin is required for tissue mechanics and full viability
title Analysis of Drosophila and mouse mutants reveals that Peroxidasin is required for tissue mechanics and full viability
title_full Analysis of Drosophila and mouse mutants reveals that Peroxidasin is required for tissue mechanics and full viability
title_fullStr Analysis of Drosophila and mouse mutants reveals that Peroxidasin is required for tissue mechanics and full viability
title_full_unstemmed Analysis of Drosophila and mouse mutants reveals that Peroxidasin is required for tissue mechanics and full viability
title_short Analysis of Drosophila and mouse mutants reveals that Peroxidasin is required for tissue mechanics and full viability
title_sort analysis of drosophila and mouse mutants reveals that peroxidasin is required for tissue mechanics and full viability
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10370120/
https://www.ncbi.nlm.nih.gov/pubmed/37503104
http://dx.doi.org/10.1101/2023.07.19.549730
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