title: Regulation of zebrafish skeletogenesis by ext2/dackel and papst1/pinscher.
abstract: 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.
authors.affiliation: MRC Centre for Developmental and Biomedical Genetics, University of Sheffield, Sheffield, United Kingdom.
authors.forename: Aurélie
authors.initials: A
authors.lastname: Clément
authors.forename: Malgorzata
authors.initials: M
authors.lastname: Wiweger
authors.forename: Sophia
authors.initials: S
authors.lastname: von der Hardt
authors.forename: Melissa A
authors.initials: MA
authors.lastname: Rusch
authors.forename: Scott B
authors.initials: SB
authors.lastname: Selleck
authors.forename: Chi-Bin
authors.initials: CB
authors.lastname: Chien
authors.forename: Henry H
authors.initials: HH
authors.lastname: Roehl
mesh_terms: D000818:Animals; D027321:Anion Transport Proteins / Q000235:genetics* / Q000502:physiology; D003001:Cloning, Molecular; D004625:Embryo, Nonmammalian; D018507:Gene Expression Regulation, Developmental; D005819:Genetic Markers; D006720:Homozygote; D019656:Loss of Heterozygosity; D018895:Microsatellite Repeats; D023421:Models, Animal; D009154:Mutation; D017351:N-Acetylglucosaminyltransferases / Q000235:genetics* / Q000502:physiology; D010012:Osteogenesis / Q000235:genetics* / Q000502:physiology; D020161:Physical Chromosome Mapping; D012333:RNA, Messenger / Q000378:metabolism; D015027:Zebrafish / Q000196:embryology / Q000235:genetics / Q000254:growth & development*; D029961:Zebrafish Proteins / Q000235:genetics* / Q000502:physiology; D000099065:Exostosin 2
chemical_list: D027321:Anion Transport Proteins; D005819:Genetic Markers; D012333:RNA, Messenger; D029961:Zebrafish Proteins; D017351:N-Acetylglucosaminyltransferases; D000099065:Exostosin 2