Journal
PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA
Volume 103, Issue 36, Pages 13333-13338Publisher
NATL ACAD SCIENCES
DOI: 10.1073/pnas.0605441103
Keywords
collagen; glycosaminoglycans; proteoglycans
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Funding
- Biotechnology and Biological Sciences Research Council [B18021] Funding Source: researchfish
- Medical Research Council [G0001033] Funding Source: researchfish
- MRC [G0001033] Funding Source: UKRI
- Biotechnology and Biological Sciences Research Council [BBS/B/10994, B18021] Funding Source: Medline
- Medical Research Council [G0001033] Funding Source: Medline
- NCI NIH HHS [P01 CA071932, CA071932] Funding Source: Medline
- NEI NIH HHS [EY014620, R01 EY014620] Funding Source: Medline
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Matrix assembly and homeostasis in collagen-rich tissues are mediated by interactions with proteoglycans (PGs) substituted with sulfated glycosaminoglycans (GAGs). The major GAG in cornea is keratan sulfate (KS), which is N-linked to one of three PG core proteins. To ascertain the importance of the carbohydrate chain sulfation step in KS functionality, we generated a strain of mice with a targeted gene deletion in Chst5, which encodes an N-acetylglucosamine-6-O-sulfotransferase that is integral to the sulfation of KS chains. Corneas of homozygous mutants were significantly thinner than those of WT or heterozygous mice. They lacked high-sulfated KS, but contained the core protein of the major corneal KSPG, lumican. Histochemically stained KSPGs coassociated with fibrillar collagen in WT corneas, but were not identified in the Chst5-null tissue. Conversely, abnormally large chondroitin sulfate/dermatan sulfate PG complexes were abundant throughout the Chst5-deficient cornea, indicating an alteration of controlled PG production in the mutant cornea. The corneal stroma of the Chst5-null mouse exhibited widespread structural alterations in collagen fibrillar architecture, including decreased interfibrillar spacing and a more spatially disorganized collagen array. The enzymatic sulfation of KS GAG chains is thus identified as a key requirement for PG biosynthesis and collagen matrix organization.
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