Disruption of Gastrulation and Heparan Sulfate Biosynthesis in EXT1-Deficient Mice
Open accessAbstract
Mutations in the EXT1 gene are responsible for human hereditary multiple exostosis type 1. The Drosophila EXT1 homologue, tout-velu, regulates Hedgehog diffusion and signaling, which play an important role in tissue patterning during both invertebrate and vertebrate development. The EXT1 protein is also required for the biosynthesis of heparan sulfate glycosaminoglycans that bind Hedgehog. In this study, we generated EXT1-deficient mice by gene targeting. EXT1 homozygous mutants fail to gastrulate and generally lack organized mesoderm and extraembryonic tissues, resulting in smaller embryos compared to normal littermates. RT-PCR analysis of markers for visceral endoderm and mesoderm development indicates the delayed and abnormal development of both of these tissues. Immunohistochemical staining revealed a visceral endoderm pattern of Indian hedgehog (Ihh) in wild-type E6.5 embryos. However, in both EXT1-deficient embryos and wild-type embryos treated with heparitinase I, Ihh failed to associate with the cells. The effect of the EXT1 deletion on heparan sulfate formation was tested by HPLC and cellular glycosyltransferase activity assays. Heparan sulfate synthesis was abolished in EXT1 -/- ES cells and decreased to less than 50% in +/- cell lines. These results indicate that EXT1 is essential for both gastrulation and heparan sulfate biosynthesis in early embryonic development.
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- Authors
- Lin, X., Wei, G., Shi, Z., Dryer, L., Esko, J. D., Wells, D. E., & Matzuk, M. M.
- Affiliations
- University of Houston (US)
- University of California San Diego (US)
- Baylor College of Medicine (US)
- Corresponding author
- Wells, Dan E.
- Venue
- Developmental Biology
- Publisher
- Elsevier BV
- Published
- 2000-08
- Volume
- 224
- Issue
- 2
- Pages
- 299-311
- ISSN
- 0012-1606 (ISSN-L)
- OpenAlex
- W2095373191
- Cited by
- 427
- References
- 54
- Citations by year
- 2026: 9 · 2025: 4 · 2024: 14 · 2023: 10 · 2022: 5 · 2021: 17 · 2020: 28 · 2019: 14 · 2018: 7 · 2017: 12 · 2016: 20 · 2015: 13 · 2014: 19 · 2013: 16 · 2012: 12
- FWCI
- 7.21
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Licence
- Locations
- Developmental Biology (publishedVersion)
- PubMed (publishedVersion)
- Funders
- National Institutes of Health (HL57345, 5r01hd027981-06)
- National Heart, Lung, and Blood Institute (HL 57345, P01HL057345)
- National Institute of General Medical Sciences (GM-33063)
- Eunice Kennedy Shriver National Institute of Child Health and Human Development (HD27981)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Cell Biology › Proteoglycans and glycosaminoglycans research
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Developmental Biology and Gene Regulation
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Hedgehog Signaling Pathway Studies
- Keywords
- EXT1, heparan sulfate biosynthesis, gastrulation, Hedgehog signaling, Indian hedgehog, mesoderm formation, visceral endoderm, extraembryonic tissues, glycosaminoglycans, early embryonic development
- MeSH terms
- Exostosin 1, Animals, Base Sequence, Cell Differentiation, Cell Membrane, Exostoses, Multiple Hereditary, Embryonic and Fetal Development, Gastrula, Heparitin Sulfate, Heparan Sulfate, Humans, Mutation, Protein Binding, Proteins, Recombination, Genetic, N-Acetylglucosaminyltransferases, DNA Primers, Gene Expression Regulation, Developmental, Insect Proteins, Reverse Transcriptase Polymerase Chain Reaction, Drosophila Proteins, Mice, Hedgehog Proteins
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