Glucuronyl C5-epimerase is crucial for epithelial cell maturation during embryonic lung development

Abstract

<jats:title>Abstract</jats:title> <jats:p>Glucuronyl C5-epimerase (Hsepi) is a key enzyme in the biosynthesis of heparan sulfate that is a sulfated polysaccharide expressed on the cell surface and in the extracellular matrix of alveolar walls and blood vessels. Targeted interruption of the Hsepi gene, Glce, in mice resulted in neonatal lethality, which is most likely due to lung atelectasis. In this study, we examined the potential mechanisms behind the defect in lung development. Histological analysis of the lungs from embryos revealed no difference in the morphology between wildtype and mutant animals up to E16.5. This suggests that the initial events leading to formation of the lung primordium and branching morphogenesis are not disturbed. However, the distal lung of E17.5–18.5 mutants is still populated by epithelial tubules, lacking the typical saccular structural characteristic of a normal E17.5 lung. Immunostaining revealed strong signals of surfactant protein-C, but a weaker signal of T1α in the mutant lungs in comparison to WT littermates, suggesting differentiation of type I alveolar epithelial cells (AT1) is impaired. One of the parameters contributed to the failure of AT1 maturation is reduced vascularization in the developing lungs.</jats:p>

Protective role of renal D-Glucuronyl C5-Epimerase (Glce) in the pathogenesis of kidney fibrosis

“…As the brosis is a complex process involving different mechanisms and factors, so far, the therapy for renal brosis is quite limited in clinic 33 . As is well known, Glce is a highly evolutionarily conserved enzyme expressed in various organs in the body 34 . Previous study established that targeting interruption of the Glce gene in mice resulted in neonatal lethality accompanied by kidney agenesis, however, there was no study reporting the association between Glce and kidney or related diseases in more detail 10 .…”

“…However, several studies demonstrated that Glce is highly expressed in human prostate cancer tissues 15 and this re ects its complex function and regulatory machinery involved in the process of oncogenesis and cancer progression. In addition to the above, some studies have pointed out that Glce may play a major role in the process of neurodevelopment 16 , embryonic lung development 17 , and endochondral ossi cation 18 , which is associated with the SMAD/ID3 and hedgehog signaling pathway. Taken together, these results match well with the experimental ndings in Glce knockout mice exhibiting growth and development defects 19 , pointing to an indispensable role of Glce in the normal growth and development of humans.…”

Physiology and Pathophysiology of Heparan Sulfate in Animal Models: Its Biosynthesis and Degradation

“…For heparin biogenesis, GLCE is unambiguously essential [99]. In the most recent study, histological analysis of the lungs in embryos revealed no difference in the morphology between wild-type and mutant animals up to E16.5 [101]. However, the distal lung of E17.5-18.5 mutants is still populated by epithelial tubules, lacking the typical saccular structural characteristic of a normal E17.5 lung.…”

Heparan sulfate fine‐tunes stromal‐epithelial communication in the prostate gland

“…The glucuronyl C5-epimerase, which converts the glucuronic acid into iduronic acid, has been shown to be important for lung epithelial cell maturation 38 .…”

“…36 The glucuronyl C5-epimerase, which converts the glucuronic acid into iduronic acid, has been shown to be important for lung epithelial cell maturation. 37 The sulfotransferases HS2ST1 and HS3ST2 add sulfates to the 2-O position of iduronic acid and to the 3-O position of the glucosamine and are relevant enzymes to HS final charge density. They are also involved in developmental anomalies 38 and in the regulation of breast cancer stem-cell function.…”