PUBLICATION
Collagen VI ablation in zebrafish causes neuromuscular defects during developmental and adult stages
- Authors
- Tonelotto, V., Consorti, C., Facchinello, N., Trapani, V., Sabatelli, P., Giraudo, C., Spizzotin, M., Cescon, M., Bertolucci, C., Bonaldo, P.
- ID
- ZDB-PUB-220813-12
- Date
- 2022
- Source
- Matrix biology : journal of the International Society for Matrix Biology 112: 39-61 (Journal)
- Registered Authors
- Bertolucci, Cristiano, Facchinello, Nicola
- Keywords
- Animal model, Collagen VI, Neuromuscular system, Skeletal development, Skeletal muscle, Zebrafish
- MeSH Terms
-
- Adrenergic Agonists
- Adult
- Albuterol
- Animals
- Collagen Type VI*/genetics
- Humans
- Muscular Diseases*/metabolism
- Zebrafish/genetics
- Zebrafish/metabolism
- Zebrafish Proteins/genetics
- PubMed
- 35961424 Full text @ Matrix Biol.
Citation
Tonelotto, V., Consorti, C., Facchinello, N., Trapani, V., Sabatelli, P., Giraudo, C., Spizzotin, M., Cescon, M., Bertolucci, C., Bonaldo, P. (2022) Collagen VI ablation in zebrafish causes neuromuscular defects during developmental and adult stages. Matrix biology : journal of the International Society for Matrix Biology. 112:39-61.
Abstract
Collagen VI (COL6) is an extracellular matrix protein exerting multiple functions in different tissues. In humans, mutations of COL6 genes cause rare inherited congenital disorders, primarily affecting skeletal muscles and collectively known as COL6-related myopathies, for which no cure is available yet. In order to get insights into the pathogenic mechanisms underlying COL6-related diseases, diverse animal models were produced. However, the roles exerted by COL6 during embryogenesis remain largely unknown. Here, we generated the first zebrafish COL6 knockout line through CRISPR/Cas9 site-specific mutagenesis of the col6a1 gene. Phenotypic characterization during embryonic and larval development revealed that lack of COL6 leads to neuromuscular defects and motor dysfunctions, together with distinctive alterations in the three-dimensional architecture of craniofacial cartilages. These phenotypic features were maintained in adult col6a1 null fish, which displayed defective muscle organization and impaired swimming capabilities. Moreover, col6a1 null fish showed autophagy defects and organelle abnormalities at both embryonic and adult stages, thus recapitulating the main features of patients affected by COL6-related myopathies. Mechanistically, lack of COL6 led to increased BMP signaling, and direct inhibition of BMP activity ameliorated the locomotor col6a1 null embryos. Finally performance of, treatment with salbutamol, a β2-adrenergic receptor agonist, elicited a significant amelioration of the neuromuscular and motility defects of col6a1 null fish embryos. Altogether, these findings indicate that this newly generated zebrafish col6a1 null line is a valuable in vivo tool to model COL6-related myopathies and suitable for drug screenings aimed at addressing the quest for effective therapeutic strategies for these disorders.
Genes / Markers
Expression
Phenotype
Mutations / Transgenics
Human Disease / Model
Sequence Targeting Reagents
Fish
Orthology
Engineered Foreign Genes
Mapping