title: Ucmaa (Grp-2) is required for zebrafish skeletal development. Evidence for a functional role of its glutamate γ-carboxylation.
abstract: UCMA (alternatively named GRP) is a novel member of the family of γ-carboxyglutamate (Gla) containing proteins that is mainly expressed in cartilage. We have used the zebrafish as a model organism to study UCMA function. Due to the whole genome duplication two Ucma genes are present in zebrafish, ucmaa and ucmab, located on chromosomes 25 and 4, respectively. UCMA gene structure, alternative splicing and protein sequence are highly conserved between mammals and zebrafish and Ucmaa and Ucmab are expressed in zebrafish skeletal tissues. Ucmaa is first detected in the notochord at 18 hpf and expression continues during notochord development. In addition, it is widely present in the developing craniofacial cartilage. In contrast, the weakly expressed Ucmab can be first detected at specific sites in the craniofacial cartilage at 96 hpf, but not in notochord. Knockdown of ucmaa leads to severe growth retardation and perturbance of skeletal development. The cartilage of the morphants has a decreased aggrecan and collagen II content. Similar malformations were observed when glutamate γ-carboxylation was inhibited by warfarin treatment, indicating that glutamate γ-carboxylation is crucial for Ucma function and pointing to a role of UCMA in the pathogenesis of "warfarin embryopathies" and other human skeletal diseases.
authors.affiliation: Center for Biochemistry, University of Cologne, 50931 Cologne, Germany.
authors.forename: Cristian Dan
authors.initials: CD
authors.lastname: Neacsu
authors.forename: Melanie
authors.initials: M
authors.lastname: Grosch
authors.forename: Mercedes
authors.initials: M
authors.lastname: Tejada
authors.forename: Andreas
authors.initials: A
authors.lastname: Winterpacht
authors.forename: Mats
authors.initials: M
authors.lastname: Paulsson
authors.forename: Raimund
authors.initials: R
authors.lastname: Wagener
authors.forename: Andreas
authors.initials: A
authors.lastname: Tagariello
mesh_terms: D015055:1-Carboxyglutamic Acid / Q000378:metabolism*; D017398:Alternative Splicing; D000595:Amino Acid Sequence; D000818:Animals; D002356:Cartilage / Q000166:cytology / Q000196:embryology / Q000254:growth & development* / Q000378:metabolism; D003001:Cloning, Molecular; D024043:Collagen Type II / Q000378:metabolism; D019295:Computational Biology; D004625:Embryo, Nonmammalian / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D047108:Embryonic Development / Q000187:drug effects; D016326:Extracellular Matrix Proteins; D005455:Fluorescent Antibody Technique; D018507:Gene Expression Regulation, Developmental; D055785:Gene Knockdown Techniques; D047908:Intracellular Signaling Peptides and Proteins; D007814:Larva; D051379:Mice; D008969:Molecular Sequence Data; D009672:Notochord / Q000166:cytology / Q000187:drug effects / Q000196:embryology / Q000378:metabolism; D010641:Phenotype; D020033:Protein Isoforms / Q000235:genetics / Q000378:metabolism; D011506:Proteins / Q000235:genetics / Q000378:metabolism; D016415:Sequence Alignment; D017385:Sequence Homology; D013194:Staining and Labeling; D013997:Time Factors; D014859:Warfarin / Q000494:pharmacology; D015027:Zebrafish / Q000196:embryology / Q000235:genetics / Q000254:growth & development* / Q000378:metabolism; D029961:Zebrafish Proteins / Q000235:genetics / Q000378:metabolism*
chemical_list: D024043:Collagen Type II; D016326:Extracellular Matrix Proteins; D047908:Intracellular Signaling Peptides and Proteins; D020033:Protein Isoforms; D011506:Proteins; C528958:Ucma protein, mouse; D029961:Zebrafish Proteins; D015055:1-Carboxyglutamic Acid; D014859:Warfarin