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

• Published in: PLoS genetics Vol. 4; no. 7; p. e1000136
• Main Authors: Clément, Aurélie, Wiweger, Malgorzata, von der Hardt, Sophia, Rusch, Melissa A, Selleck, Scott B, Chien, Chi-Bin, Roehl, Henry H
• Format: Journal Article
• Language: English
• Published: United States Public Library of Science 01.07.2008; Public Library of Science (PLoS)
• 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
• ISSN: 1553-7404; 1553-7390; 1553-7404
• DOI: 10.1371/journal.pgen.1000136

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.