Altered heparan sulfate structure in mice with deleted NDST3 gene function.
We report the generation and analysis of mutant mice bearing a targeted disruption of the heparan sulfate (HS)-modifying enzyme GlcNAc N-deacetylase/N-sulfotransferase 3 (NDST3). NDST3(-/-) mice develop normally, are fertile, and show only subtle hematological and behavioral abnormalities in agreement with only moderate HS undersulfation. Compound mutant mice made deficient in NDST2;NDST3 activities also develop normally, showing that both isoforms are not essential for development. In contrast, NDST1(-/-);NDST3(-/-) compound mutant embryos display developmental defects caused by severe HS undersulfation, demonstrating NDST3 contribution to HS synthesis in the absence of NDST1. Moreover, analysis of HS composition in dissected NDST3 mutant adult brain revealed regional changes in HS sulfation, indicating restricted NDST3 activity on nascent HS in defined wild-type tissues. Taken together, we show that NDST3 function is not essential for development or adult homeostasis despite contributing to HS synthesis in a region-specific manner and that the loss of NDST3 function is compensated for by the other NDST isoforms to a varying degree.
Pallerla
Srinivas R
SR
Department of General Zoology and Genetics, Westfälische Wilhelms-Universität Münster, Münster, Germany.
Lawrence
Roger
R
Lewejohann
Lars
L
Pan
Yi
Y
Fischer
Tobias
T
Schlomann
Uwe
U
Zhang
Xin
X
Esko
Jeffrey D
JD
Grobe
Kay
K
D000818:Animals; D001921:Brain / Q000196:embryology; D017353:Gene Deletion; D018507:Gene Expression Regulation, Developmental; D006497:Heparan Sulfate / Q000378:metabolism*; D006706:Homeostasis; D051379:Mice; D008810:Mice, Inbred C57BL; D008954:Models, Biological; D008957:Models, Genetic; D009154:Mutation; D020033:Protein Isoforms; D011995:Recombination, Genetic; D015238:Sulfotransferases / Q000737:chemistry / Q000378:metabolism / Q000502:physiology*; D014018:Tissue Distribution
D006497:Heparan Sulfate; D020033:Protein Isoforms; D015238:Sulfotransferases; C021350:heparitin sulfotransferase