PUBLICATION
Enhanced lysosomal exocytosis and altered growth factor signaling are associated with cartilage pathology in a zebrafish model of MPSIVA
- Authors
- Lee, J.J., Lu, P.N., Dukes-Rimsky, L., Jeter, C., Colonna, M.B., Poplawski, A.B., Arno, G., Hallman, J., Underwood, C., Basu, A., Pollard, L., Weiss, R.J., Steet, R., Flanagan-Steet, H.
- ID
- ZDB-PUB-260126-9
- Date
- 2026
- Source
- Disease models & mechanisms : (Journal)
- Registered Authors
- Flanagan-Steet, Heather, Steet, Richard
- Keywords
- Cartilage, Cathepsin, Exocytosis, Lysosomes, MPSIVA, Zebrafish
- Datasets
- GEO:GSE300957
- MeSH Terms
-
- Animals
- Bone Morphogenetic Proteins/metabolism
- Cartilage*/metabolism
- Cartilage*/pathology
- Cathepsins/metabolism
- Disease Models, Animal
- Exocytosis*
- Glycosaminoglycans/metabolism
- Intercellular Signaling Peptides and Proteins*/metabolism
- Lysosomes*/metabolism
- Mucopolysaccharidosis IV*/metabolism
- Mucopolysaccharidosis IV*/pathology
- Mutation/genetics
- Signal Transduction*
- Sulfatases/metabolism
- Transforming Growth Factor beta/metabolism
- Zebrafish/embryology
- Zebrafish/metabolism
- Zebrafish Proteins/metabolism
- PubMed
- 41582713 Full text @ Dis. Model. Mech.
Citation
Lee, J.J., Lu, P.N., Dukes-Rimsky, L., Jeter, C., Colonna, M.B., Poplawski, A.B., Arno, G., Hallman, J., Underwood, C., Basu, A., Pollard, L., Weiss, R.J., Steet, R., Flanagan-Steet, H. (2026) Enhanced lysosomal exocytosis and altered growth factor signaling are associated with cartilage pathology in a zebrafish model of MPSIVA. Disease models & mechanisms. :.
Abstract
Optimal lysosomal function is essential for early tissue development. This is evidenced by the large number of inherited disorders, collectively called the lysosomal storage disorders (LSDs), caused by lysosomal dysfunction. While it is clear that macromolecular accumulation adversely impacts tissue development, the breadth of downstream pathways contributing to pathology has yet to be elucidated. Multiple studies indicate mechanisms beyond lysosomal storage also profoundly influence early tissue formation. Of these, abnormal growth factor signaling has been linked to pathology in several different LSDs. Recent work in a zebrafish model of sialidosis demonstrated that mislocalizing lysosomal cathepsins by increased exocytosis disrupts the TGF-ß related signaling pathways that control skeletal formation. Here we show loss of the enzyme galns (N-acetyl galactosamine-6-sulfatase) also enhances lysosomal exocytosis in developing cartilage of mutant zebrafish. Unlike sialidosis, however, in galns mutants increased exocytosis was associated with reduced cathepsin activity, lower levels of TGFß and BMP signaling, and altered abundance of intra- and extracellular glycosaminoglycans. Together these data highlight a role for lysosomal exocytosis and protease-mediated alterations in growth factor signaling in onset of MPSIVA skeletal pathology.
Genes / Markers
Expression
Phenotype
Mutations / Transgenics
Human Disease / Model
Sequence Targeting Reagents
Fish
Orthology
Engineered Foreign Genes
Mapping