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PMID:19834066

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Citation

Flanagan-Steet, H, Sias, C and Steet, R (2009) Altered chondrocyte differentiation and extracellular matrix homeostasis in a zebrafish model for mucolipidosis II. Am. J. Pathol. 175:2063-75

Abstract

Mucolipidosis 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.

Links

PubMed PMC2774070 Online version:10.2353/ajpath.2009.090210

Keywords

Animals; Cell Differentiation/physiology; Child; Chondrocytes/cytology; Chondrocytes/physiology; Collagen Type II/genetics; Collagen Type II/metabolism; Craniofacial Abnormalities; Disease Models, Animal; Extracellular Matrix/metabolism; Homeostasis; Humans; Hydrolases/metabolism; Lysosomes/enzymology; Mannosephosphates/biosynthesis; Morphogenesis; Motor Activity/physiology; Mucolipidoses/genetics; Mucolipidoses/metabolism; Mucolipidoses/physiopathology; Oligonucleotides, Antisense/genetics; Oligonucleotides, Antisense/metabolism; Otolithic Membrane/cytology; Otolithic Membrane/embryology; Phenotype; SOX9 Transcription Factor/genetics; SOX9 Transcription Factor/metabolism; Smad2 Protein/genetics; Smad2 Protein/metabolism; Transferases (Other Substituted Phosphate Groups)/genetics; Transferases (Other Substituted Phosphate Groups)/metabolism; Zebrafish/abnormalities; Zebrafish/anatomy & histology; Zebrafish/embryology; Zebrafish/physiology; Zebrafish Proteins/genetics; Zebrafish Proteins/metabolism

Significance

Annotations

Gene product Qualifier GO Term Evidence Code with/from Aspect Extension Notes Status

DANRE:GNPTA

involved_in

GO:0002063: chondrocyte development

ECO:0000315: mutant phenotype evidence used in manual assertion

ZFIN:ZDB-MRPHLNO-100302-2

P

Seeded From UniProt

complete

DANRE:GNPTA

involved_in

GO:0002063: chondrocyte development

ECO:0000315: mutant phenotype evidence used in manual assertion

ZFIN:ZDB-MRPHLNO-100302-1

P

Seeded From UniProt

complete

DANRE:GNPTA

involved_in

GO:0048701: embryonic cranial skeleton morphogenesis

ECO:0000315: mutant phenotype evidence used in manual assertion

ZFIN:ZDB-MRPHLNO-100302-2

P

Seeded From UniProt

complete

DANRE:GNPTA

involved_in

GO:0048701: embryonic cranial skeleton morphogenesis

ECO:0000315: mutant phenotype evidence used in manual assertion

ZFIN:ZDB-MRPHLNO-100302-1

P

Seeded From UniProt

complete


See also

References

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