Dermatan Sulfate-Free Mice Display Embryological Defects and Are Neonatal Lethal Despite Normal Lymphoid and Non-Lymphoid Organogenesis.
The epimerization of glucuronic acid into iduronic acid adds structural variability to chondroitin/dermatan sulfate polysaccharides. Iduronic acid-containing domains play essential roles in processes such as coagulation, chemokine and morphogen modulation, collagen maturation, and neurite sprouting. Therefore, we generated and characterized, for the first time, mice deficient in dermatan sulfate epimerase 1 and 2, two enzymes uniquely involved in dermatan sulfate biosynthesis. The resulting mice, termed DKO mice, were completely devoid of iduronic acid, and the resulting chondroitin sulfate chains were structurally different from the wild type chains, from which a different protein binding specificity can be expected. As a consequence, a vast majority of the DKO mice died perinatally, with greatly variable phenotypes at birth or late embryological stages such as umbilical hernia, exencephaly and a kinked tail. However, a minority of embryos were histologically unaffected, with apparently normal lung and bone/cartilage features. Interestingly, the binding of the chemokine CXCL13, an important modulator of lymphoid organogenesis, to mouse DKO embryonic fibroblasts was impaired. Nevertheless, the development of the secondary lymphoid organs, including the lymph nodes and spleen, was normal. Altogether, our results indicate an important role of dermatan sulfate in embryological development and perinatal survival.
Department of Experimental Medical Science, Lund University, Lund, Sweden.
Xanthi N
XN
Stachtea
Department of Experimental Medical Science, Lund University, Lund, Sweden.
Emil
E
Tykesson
Department of Biochemistry, Radboud Institute for Molecular Life Sciences, Radboud University Medical Center, Nijmegen, the Netherlands.
Toin H
TH
van Kuppevelt
Department of Pathology, The National Veterinary Institute (SVA), SE 75189, Uppsala, Sweden.
Ricardo
R
Feinstein
Department of Experimental Medical Science, Lund University, Lund, Sweden.
Anders
A
Malmström
Department of Molecular Cell Biology and Immunology, VU University Medical Center, Amsterdam, the Netherlands.
Rogier M
RM
Reijmers
Department of Experimental Medical Science, Lund University, Lund, Sweden.
Marco
M
Maccarana
D000818:Animals; D000831:Animals, Newborn; D015153:Blotting, Western; D002238:Carbohydrate Epimerases / Q000172:deficiency* / Q000235:genetics; D002478:Cells, Cultured; D054382:Chemokine CXCL13 / Q000378:metabolism; D002809:Chondroitin Sulfates / Q000378:metabolism; D003871:Dermatan Sulfate / Q000378:metabolism*; D004187:Disaccharides / Q000378:metabolism; D004622:Embryo, Mammalian / Q000166:cytology / Q000196:embryology / Q000378:metabolism*; D005347:Fibroblasts / Q000166:cytology / Q000378:metabolism; D008221:Lymphoid Tissue / Q000254:growth & development* / Q000378:metabolism; D057507:Mice, 129 Strain; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008856:Microscopy, Fluorescence; D038081:Organogenesis; D011485:Protein Binding
D054382:Chemokine CXCL13; D004187:Disaccharides; D003871:Dermatan Sulfate; D002809:Chondroitin Sulfates; D002238:Carbohydrate Epimerases; C544542:dermatan sulfate epimerase 1, mouse