|ZFIN ID: ZDB-PUB-091023-51|
Your Input Welcome
Thank you for submitting comments. Your input has been emailed to ZFIN curators who may contact you if additional information is required.
Oops. Something went wrong. Please try again later.
Altered Chondrocyte Differentiation and Extracellular Matrix Homeostasis in a Zebrafish Model for Mucolipidosis II
Flanagan-Steet, H., Sias, C., and Steet, R.
|Source:||The American journal of pathology 175(5): 2063-2075 (Journal)|
|PubMed:||19834066 Full text @ Am. J. Pathol.|
Flanagan-Steet, H., Sias, C., and Steet, R. (2009) Altered Chondrocyte Differentiation and Extracellular Matrix Homeostasis in a Zebrafish Model for Mucolipidosis II. The American journal of pathology. 175(5):2063-2075.
ABSTRACTMucolipidosis II (ML-II) is a pediatric disorder caused by defects in the biosynthesis of mannose 6-phosphate, the carbohydrate recognition signal responsible for targeting certain acid hydrolases to lysosomes. The mechanisms underlying the developmental defects of ML-II are largely unknown due in part to the lack of suitable animal models. To overcome these limitations, we developed a model for ML-II in zebrafish by inhibiting the expression of N-acetylglucosamine-1-phosphotransferase, the enzyme that initiates mannose 6-phosphate biosynthesis. Morphant embryos manifest craniofacial defects, impaired motility, and abnormal otolith and pectoral fin development. Decreased mannose phosphorylation of several lysosomal glycosidases was observed in morphant lysates, consistent with the reduction in phosphotransferase activity. Investigation of the craniofacial defects in the morphants uncovered striking changes in the timing and localization of both type II collagen and Sox9 expression, suggestive of an accelerated chondrocyte differentiation program. Accumulation of type II collagen was also noted within misshapen cartilage elements at later stages of development. Furthermore, we observed abnormal matrix formation and calcium deposition in morphant otoliths. Collectively, these data provide new insight into the developmental pathology of ML-II and suggest that altered production and/or homeostasis of extracellular matrix proteins are integral to the disease process. These findings highlight the potential of the zebrafish system in studying lysosomal disease pathogenesis.