Regulation of zebrafish skeletogenesis by ext2/dackel and papst1/pinscher

Mutations in human Exostosin genes (EXTs) confer a disease called Hereditary Multiple Exostoses (HME) that affects 1 in 50,000 among the general population. Patients with HME have a short stature and develop osteochondromas during childhood. Here we show that two zebrafish mutants, dackel (dak) and...

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Bibliographic Details
Published in:PLoS genetics 2008-07, Vol.4 (7), p.e1000136-e1000136
Main Authors: Clément, Aurélie, Wiweger, Malgorzata, von der Hardt, Sophia, Rusch, Melissa A, Selleck, Scott B, Chien, Chi-Bin, Roehl, Henry H
Format: Article
Language:English
Subjects:
Animals
Anion Transport Proteins - genetics
Anion Transport Proteins - physiology
Bones
Cloning, Molecular
Colleges & universities
Danio rerio
Developmental Biology/Cell Differentiation
Developmental Biology/Morphogenesis and Cell Biology
Embryo, Nonmammalian
Gene Expression Regulation, Developmental
Genetic Markers
Genetics and Genomics/Disease Models
Histology
Homozygote
Loss of Heterozygosity
Microsatellite Repeats
Models, Animal
Mutation
N-Acetylglucosaminyltransferases - genetics
N-Acetylglucosaminyltransferases - physiology
Osteogenesis - genetics
Osteogenesis - physiology
Physical Chromosome Mapping
RNA, Messenger - metabolism
Zebrafish
Zebrafish - embryology
Zebrafish - genetics
Zebrafish - growth & development
Zebrafish Proteins - genetics
Zebrafish Proteins - physiology
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Summary:Mutations in human Exostosin genes (EXTs) confer a disease called Hereditary Multiple Exostoses (HME) that affects 1 in 50,000 among the general population. Patients with HME have a short stature and develop osteochondromas during childhood. Here we show that two zebrafish mutants, dackel (dak) and pinscher (pic), have cartilage defects that strongly resemble those seen in HME patients. We have previously determined that dak encodes zebrafish Ext2. Positional cloning of pic reveals that it encodes a sulphate transporter required for sulphation of glycans (Papst1). We show that although both dak and pic are required during cartilage morphogenesis, they are dispensable for chondrocyte and perichondral cell differentiation. They are also required for hypertrophic chondrocyte differentiation and osteoblast differentiation. Transplantation analysis indicates that dak(-/-) cells are usually rescued by neighbouring wild-type chondrocytes. In contrast, pic(-/-) chondrocytes always act autonomously and can disrupt the morphology of neighbouring wild-type cells. These findings lead to the development of a new model to explain the aetiology of HME.
ISSN:1553-7404
1553-7390
1553-7404
DOI:10.1371/journal.pgen.1000136