Mouse development is not obviously affected by the absence of dermatan sulfate epimerase 2 in spite of a modified brain dermatan sulfate composition

Abstract

Dermatan sulfate epimerase 2 (DS-epi2), together with its homolog DS-epi1, transform glucuronic acid into iduronic acid in DS polysaccharide chains. Iduronic acid gives DS increased chain flexibility and promotes protein binding. DS-epi2 is ubiquitously expressed and is the predominant epimerase in the brain. Here, we report the generation and initial characterization of DS-epi2 null mice. DS-epi2-deficient mice showed no anatomical, histological or morphological abnormalities. The body weights and lengths of mutated and wild-type littermates were indistinguishable. They were fertile and had a normal lifespan. Chondroitin sulfate (CS)/DS isolated from the newborn mutated mouse brains had a 38% reduction in iduronic acid compared with wild-type littermates, and compositional analysis revealed a decrease in 4-O-sulfate and an increase in 6-O-sulfate containing structures. Despite the reduction in iduronic acid, the adult DS-epi2-/- brain showed normal extracellular matrix features by immunohistological stainings. We conclude that DS-epi1 compensates in vivo for the loss of DS-epi2. These results extend previous findings of the functional redundancy of brain extracellular matrix components.

Iduronic Acid in Chondroitin/Dermatan Sulfate Affects Directional Migration of Aortic Smooth Muscle Cells

“…1B), which can be ascribed to DS-epi2 [5]. This result is similar to the previously reported residual activity measured in DS-epi1−/− embryonic fibroblasts [22]. To assess the structural variations in the CS/DS chains, WT and DS-epi1−/− cell media were supplemented with 35 [S]-sulfate and labeled PGs were isolated and analyzed.…”

Human Genetic Disorders and Knockout Mice Deficient in Glycosaminoglycan

“…Although no significant differences were observed in the content of collagen between Dse −/− and the wild type, the ultrastructure of collagen fibrils in the dermis and hypodermis was thicker in the deficient mice than in the wild type, and a decline in their mechanical strength was also noted in the deficient mice. On the other hand, no morphological or histological abnormalities have been reported in mice targeted with the disruption of DS epimerase-2 encoded by Dsel [93]. In addition, 4- O -sulfation of the DS chain was decreased in the brain of Dse2 −/− , whereas the adult Dse2 −/− brain had normal structures in the extracellular matrix.…”

“…In addition, 4- O -sulfation of the DS chain was decreased in the brain of Dse2 −/− , whereas the adult Dse2 −/− brain had normal structures in the extracellular matrix. The function of Dse2 appears to be compensated by Dse1 [93]. …”

Biological functions of iduronic acid in chondroitin/dermatan sulfate

“…In the brain, the activity is low and no activity is found in serum . By analyzing the total activity in tissues and mouse embryonic fibroblasts of DS‐epi1 −/− and DS‐epi2 −/− mice, it is possible to show that DS‐epi1 is the predominant epimerase in most tissues, whereas DS‐epi2 is the main epimerase in the brain . DS‐epi2 also has a relatively high expression in the kidney.…”

“…DS‐epi2 −/− mice do not show any evident phenotype . The brain was analyzed because DS‐epi2 is the predominant epimerase in this tissue . Accordingly, DS‐epi2 −/− brains had a 90% reduction in epimerase activity.…”