Dermatan sulfate epimerase 1 deficient mice as a model for human abdominal wall defects

Abstract

BackgroundDermatan sulfate (DS) is a highly sulfated polysaccharide with a variety of biological functions in extracellular matrix organization and processes such as tumorigenesis and wound healing. A distinct feature of DS is the presence of iduronic acid, produced by the two enzymes, DS-epimerase 1 and 2, which are encoded by Dse and Dsel, respectively.MethodsWe have previously shown that Dse knockout (KO) mice in a mixed C57BL/6–129/SvJ background have an altered collagen matrix structure in skin. In the current work we studied Dse KO mice in a pure NFR genetic background.ResultsDse KO embryos and newborns had kinked tails and histological staining revealed significantly thicker epidermal layers in Dse KO mice when compared with heterozygote (Het) or wild-type (WT) littermates. Immunochemical analysis of the epidermal layers in newborn pups showed increased expression of keratin 5 in the basal layer and keratin 1 in the spinous layer. In addition, we observed an abdominal wall defect with herniated intestines in 16% of the Dse KO embryos. Other, less frequent, developmental defects were exencephaly and spina bifida.ConclusionWe conclude that the combination of defective collagen structure in the dermis and imbalanced keratinocyte maturation could be responsible for the observed developmental defects in Dse KO mice. In addition, we propose that Dse KO mice could be used as a model in pathogenetic studies of human fetal abdominal wall defects. Birth Defects Research (Part A) 100:712–720, 2014. © 2014 Wiley Periodicals, Inc.

Dermatan Sulfate-Free Mice Display Embryological Defects and Are Neonatal Lethal Despite Normal Lymphoid and Non-Lymphoid Organogenesis

“…Two mouse strains carrying the functionally inactivated Dse or Dsel gene, resulting in complete loss of dermatan sulfate epimerase-1 (DS-epi1) or -2 (DS-epi2) activity, respectively, have previously been generated in our laboratory [ 5 , 7 ]. DS-epi1 knockout (KO) mice are viable in a mixed C57BL/6-129/SvJ genetic background but are perinatally lethal in a pure C57BL/6 or NFR genetic background [ 6 ]. DS-epi2 -/- mice were previously analyzed in a mixed C57BL/6-129/SvJ genetic background.…”

“…DS-epi1 is the major epimerase in most tissues, while DS-epi2 is dominant in brain tissue. Interestingly, DS-epi1 deficient mice revealed a fragile skin phenotype, a smaller body size and several malformations [ 5 , 6 ]. In contrast, the loss of DS-epi2 produced completely normal offspring [ 7 ].…”

Recent Advances in the Pathophysiology of Musculocontractural Ehlers-Danlos Syndrome

“…Furthermore, a small portion of DS-epi1 −/− embryos showed an abdominal wall defect with herniated intestines, exencephaly and spina bifida. Defective collagen structure in the dermis and imbalanced keratocyte maturation were presumed to cause developmental defects in DS-epi1 −/− mice [46]. These observations indicate that DS-epi1 −/− mice may constitute a useful model of mcEDS-DSE.…”

“…The numbers of IdoUA blocks were dramatically reduced in DS side chains of decorin-PG and biglycan-PG from the skin of DS-epi1 −/− mice [45], which suggests that DS-epi1 mainly synthesizes IdoUA blocks in vivo. DS-epi1 −/− embryos and newborn mice showed kinked tails, which is a common feature in Chst14 −/− mice [38]; the DS-epi1 −/− embryos and newborn mice also showed significantly thicker epidermal layers through histological staining, compared with heterozygous or wild-type littermates [45,46]. Immunohistochemical staining of epidermal layers in DS-epi1 −/− newborns showed increased expression of keratin 5 in the basal layer and keratin 1 in the spinous layer [46].…”

“…DS-epi1 −/− embryos and newborn mice showed kinked tails, which is a common feature in Chst14 −/− mice [38]; the DS-epi1 −/− embryos and newborn mice also showed significantly thicker epidermal layers through histological staining, compared with heterozygous or wild-type littermates [45,46]. Immunohistochemical staining of epidermal layers in DS-epi1 −/− newborns showed increased expression of keratin 5 in the basal layer and keratin 1 in the spinous layer [46]. Furthermore, a small portion of DS-epi1 −/− embryos showed an abdominal wall defect with herniated intestines, exencephaly and spina bifida.…”