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Chondroitin/dermatan sulfate glycosyltransferase genes are essential for craniofacial development
Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Organismal Biology, Evolution and Developmental Biology. Department of Cellular, Computational and Integrative Biology (CIBIO), University of Trento, Trento, Italy.ORCID iD: 0000-0002-8691-8650
Genes & Human Disease Research Program, Oklahoma Medical Research Foundation, Oklahoma City, Oklahoma, United States of America .ORCID iD: 0000-0002-0429-1904
Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Organismal Biology, Evolution and Developmental Biology.ORCID iD: 0000-0002-3619-0796
Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Organismal Biology, Evolution and Developmental Biology.ORCID iD: 0000-0001-9704-6336
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2022 (English)In: PLOS Genetics, ISSN 1553-7390, E-ISSN 1553-7404, Vol. 18, no 2, article id e1010067Article in journal (Refereed) Published
Abstract [en]

Chondroitin/dermatan sulfate (CS/DS) proteoglycans are indispensable for animal development and homeostasis but the large number of enzymes involved in their biosynthesis have made CS/DS function a challenging problem to study genetically. In our study, we generated loss-of-function alleles in zebrafish genes encoding CS/DS biosynthetic enzymes and characterized the effect on development in single and double mutants. Homozygous mutants in chsy1, csgalnact1a, csgalnat2, chpfa, ust and chst7, respectively, develop to adults. However, csgalnact1a-/- fish develop distinct craniofacial defects while the chsy1-/- skeletal phenotype is milder and the remaining mutants display no gross morphological abnormalities. These results suggest a high redundancy for the CS/DS biosynthetic enzymes and to further reduce CS/DS biosynthesis we combined mutant alleles. The craniofacial phenotype is further enhanced in csgalnact1a-/-;chsy1-/- adults and csgalnact1a-/-;csgalnact2-/- larvae. While csgalnact1a-/-;csgalnact2-/- was the most affected allele combination in our study, CS/DS is still not completely abolished. Transcriptome analysis of chsy1-/-, csgalnact1a-/- and csgalnact1a-/-;csgalnact2-/- larvae revealed that the expression had changed in a similar way in the three mutant lines but no differential expression was found in any of fifty GAG biosynthesis enzymes identified. Thus, zebrafish larvae do not increase transcription of GAG biosynthesis genes as a consequence of decreased CS/DS biosynthesis. The new zebrafish lines develop phenotypes similar to clinical characteristics of several human congenital disorders making the mutants potentially useful to study disease mechanisms and treatment.

Place, publisher, year, edition, pages
Public Library of Science (PLoS), 2022. Vol. 18, no 2, article id e1010067
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Biochemistry and Molecular Biology
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URN: urn:nbn:se:uu:diva-473635DOI: 10.1371/journal.pgen.1010067ISI: 001004241700001PubMedID: 35192612OAI: oai:DiVA.org:uu-473635DiVA, id: diva2:1655075
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Science for Life Laboratory, SciLifeLab
Note

Correction in: The PLOS Genetics, vol. 18, issue 5, Article no e1010242.

DOI: 10.1371/journal.pgen.1010242

Available from: 2022-04-29 Created: 2022-04-29 Last updated: 2023-10-10Bibliographically approved

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Habicher, JudithWaldmann, LauraSnitting, DanielAllalou, AminZhang, HanqingGhanem, AbdurrahmanÖhman, CarolineDierker, TabeaKjellén, LenaLedin, Johan

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Habicher, JudithVarshney, Gaurav K.Waldmann, LauraSnitting, DanielAllalou, AminZhang, HanqingGhanem, AbdurrahmanÖhman, CarolineDierker, TabeaKjellén, LenaBurgess, Shawn M.Ledin, Johan
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Evolution and Developmental BiologyScience for Life Laboratory, SciLifeLabComputerized Image Analysis and Human-Computer InteractionMolecular Tools and Functional GenomicsDepartment of Medical Biochemistry and MicrobiologyApplied Material ScienceDepartment of Organismal Biology
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