Similar Datasets
Project description:Heparan sulfate (HS) regulation of FGFR function, which is essential for salivary gland (SG) development, is determined by the immense structural diversity of sulfated HS domains. 3-O-sulfotransferases generate highly 3-O-sulfated HS domains (3-O-HS), and Hs3st3a1 and Hs3st3b1 are enriched in myoepithelial cells (MECs) that produce basement membrane (BM) and are a growth factor signaling hub. Hs3st3a1;Hs3st3b1 double-knockout (DKO) mice generated to investigate 3-O-HS regulation of MEC function and growth factor signaling show loss of specific highly 3-O-HS and increased FGF/FGFR complex binding to HS. During development, this increases FGFR-, BM- and MEC-related gene expression, while in adult, it reduces MECs, increases BM and disrupts acinar polarity, resulting in salivary hypofunction. Defined 3-O-HS added to FGFR pulldown assays and primary organ cultures modulates FGFR signaling to regulate MEC BM synthesis, which is critical for secretory unit homeostasis and acinar function. Understanding how sulfated HS regulates development will inform the use of HS mimetics in organ regeneration.
| S-EPMC11365954 | biostudies-literature
Project description:FGF signaling is essential for salivary gland (SG) development and heparan sulfate (HS) regulation of FGFR function is determined by immense structural diversity of sulfated HS domains. The basement membrane (BM), containing HS proteoglycans, collagens and laminins, separates epithelia from stroma and controls growth factor-matrix cross-talk. 3-O-sulfotransferases generate highly 3-O-sulfated HS domains (3-O-HS) and Hs3st3a1 and Hs3st3b1 are enriched in myoepithelial cells (MECs), which produce BM and are a growth factor signaling hub. To investigate 3-O-HS regulation of MEC function and growth factor signaling, we generated Hs3st3a1;Hs3st3b1 double knockout (DKO) mice. The DKO HS loses specific highly 3-O-sulfated tetrasaccharides, which increases FGF/FGFR-complex binding to HS. During development this leads to increased FGFR-, BM- and MEC-related gene expression. However, in adult DKO SGs the secretory units containing acinar and MECs, have reduced MECs, increased BM and disrupted acinar polarity, resulting in salivary hypofunction. We used defined 3-O-sulfated-HS in FGFR pulldown assays and primary organ cultures to investigate 3-O-HS-dependent mechanisms regulating MEC development. We find that 3-O-HS modulates FGFR signaling to regulate MEC BM synthesis which is critical for secretory unit homeostasis and acinar function. Understanding how sulfated HS regulates development will inform the use of HS mimetics in organ regeneration.
2024-08-02 | GSE235184 | GEO
Project description:FGF signaling is essential for salivary gland (SG) development and heparan sulfate (HS) regulation of FGFR function is determined by immense structural diversity of sulfated HS domains. The basement membrane (BM), containing HS proteoglycans, collagens and laminins, separates epithelia from stroma and controls growth factor-matrix cross-talk. 3-O-sulfotransferases generate highly 3-O-sulfated HS domains (3-O-HS) and Hs3st3a1 and Hs3st3b1 are enriched in myoepithelial cells (MECs), which produce BM and are a growth factor signaling hub. To investigate 3-O-HS regulation of MEC function and growth factor signaling, we generated Hs3st3a1;Hs3st3b1 double knockout (DKO) mice. The DKO HS loses specific highly 3-O-sulfated tetrasaccharides, which increases FGF/FGFR-complex binding to HS. During development this leads to increased FGFR-, BM- and MEC-related gene expression. However, in adult DKO SGs the secretory units containing acinar and MECs, have reduced MECs, increased BM and disrupted acinar polarity, resulting in salivary hypofunction. We used defined 3-O-sulfated-HS in FGFR pulldown assays and primary organ cultures to investigate 3-O-HS-dependent mechanisms regulating MEC development. We find that 3-O-HS modulates FGFR signaling to regulate MEC BM synthesis which is critical for secretory unit homeostasis and acinar function. Understanding how sulfated HS regulates development will inform the use of HS mimetics in organ regeneration.
2024-08-02 | GSE235185 | GEO
Project description:Specific 3-O-sulfated heparan sulfate domains regulate salivary gland basement membrane metabolism and epithelial differentiation
| PRJNA984724 | ENA
Project description:Specific 3-O-sulfated heparan sulfate domains regulate salivary gland basement membrane metabolism and epithelial differentiation [female]
| PRJNA984729 | ENA
Project description:Specific 3-O-sulfated heparan sulfate domains regulate salivary gland basement membrane metabolism and epithelial differentiation [male]
| PRJNA984728 | ENA
Project description:Heparan sulfate (HS) serves as a cell-surface co-receptor for growth factors, morphogens, and chemokines. These HS and protein binding events depend on the fine structure and distribution of domains along an HS chain. A given domain can vary in terms of uronic acid epimer, N- and O-sulfate, and N-acetate content. The most highly sulfated regions of HS chains, N-sulfated (NS) domains, play prominent roles in HS and protein binding. We have analyzed HS oligosaccharides from various mammalian sources and provide evidence that NS domains residing at the nonreducing end (NRE) are, on average, longer than those residing in the internal regions of the chain. Additionally, they are more highly sulfated than their internal counterparts. These features are independent of the sulfation pattern of the bulk HS chains. From disaccharide analysis, it is clear that NS domains do not always occupy HS NREs. However, when they do, they tend to terminate in a subset of N-sulfated disaccharides. Our observations are consistent with a significant role of NRE NS domains in HS-growth factor interactions.
| S-EPMC2881759 | biostudies-literature
Project description:BackgroundLipoprotein lipase (Lpl) acts on triglyceride-rich lipoproteins in the peripheral circulation, liberating free fatty acids for energy metabolism or storage. This essential enzyme is synthesized in parenchymal cells of adipose tissue, heart, and skeletal muscle and migrates to the luminal side of the vascular endothelium where it acts upon circulating lipoproteins. Prior studies suggested that Lpl is immobilized by way of heparan sulfate proteoglycans on the endothelium, but genetically altering endothelial cell heparan sulfate had no effect on Lpl localization or lipolysis. The objective of this study was to determine if extracellular matrix proteoglycans affect Lpl distribution and triglyceride metabolism.Methods and findingsWe examined mutant mice defective in collagen XVIII (Col18), a heparan sulfate proteoglycan present in vascular basement membranes. Loss of Col18 reduces plasma levels of Lpl enzyme and activity, which results in mild fasting hypertriglyceridemia and diet-induced hyperchylomicronemia. Humans with Knobloch Syndrome caused by a null mutation in the vascular form of Col18 also present lower than normal plasma Lpl mass and activity and exhibit fasting hypertriglyceridemia.ConclusionsThis is the first report demonstrating that Lpl presentation on the lumenal side of the endothelium depends on a basement membrane proteoglycan and demonstrates a previously unrecognized phenotype in patients lacking Col18.
| S-EPMC2978080 | biostudies-literature
Project description:Heparan sulfate 3-O-sulfotransferases generate highly sulfated but rare 3-O-sulfated heparan sulfate (HS) epitopes on cell surfaces and in the extracellular matrix. Previous ex vivo experiments suggested functional redundancy exists among the family of seven enzymes but that Hs3st3a1 and Hs3st3b1 sulfated HS increases epithelial FGFR signaling and morphogenesis. Single-cell RNAseq analysis of control SMGs identifies increased expression of Hs3st3a1 and Hs3st3b1 in endbud and myoepithelial cells, both of which are progenitor cells during development and regeneration. To analyze their in vivo functions, we generated both Hs3st3a1-/- and Hs3st3b1-/- single knockout mice, which are viable and fertile. Salivary glands from both mice have impaired fetal epithelial morphogenesis when cultured with FGF10. Hs3st3b1-/- mice have reduced intact SMG branching morphogenesis and reduced 3-O-sulfated HS in the basement membrane. Analysis of HS biosynthetic enzyme transcription highlighted some compensatory changes in sulfotransferases expression early in development. The overall glycosaminoglycan composition of adult control and KO mice were similar, although HS disaccharide analysis showed increased N- and non-sulfated disaccharides in Hs3st3a1-/- HS. Analysis of adult KO gland function revealed normal secretory innervation, but without stimulation there was an increase in frequency of drinking behavior in both KO mice, suggesting basal salivary hypofunction, possibly due to myoepithelial dysfunction. Understanding how 3-O-sulfation regulates myoepithelial progenitor function will be important to manipulate HS-binding growth factors to enhance tissue function and regeneration.
| S-EPMC8629026 | biostudies-literature
Project description:Heparan sulfate-modified proteoglycans (HSPGs) are important regulators of signaling and molecular recognition at the cell surface and in the extracellular space. Disruption of HSPG core proteins, HS-synthesis, or HS-degradation can have profound effects on growth, patterning, and cell survival. The Drosophila neuromuscular junction provides a tractable model for understanding the activities of HSPGs at a synapse that displays developmental and activity-dependent plasticity. Muscle cell-specific knockdown of HS biosynthesis disrupted the organization of a specialized postsynaptic membrane, the subsynaptic reticulum (SSR), and affected the number and morphology of mitochondria. We provide evidence that these changes result from a dysregulation of macroautophagy (hereafter referred to as autophagy). Cellular and molecular markers of autophagy are all consistent with an increase in the levels of autophagy in the absence of normal HS-chain biosynthesis and modification. HS production is also required for normal levels of autophagy in the fat body, the central energy storage and nutritional sensing organ in Drosophila. Genetic mosaic analysis indicates that HS-dependent regulation of autophagy occurs non-cell autonomously, consistent with HSPGs influencing this cellular process via signaling in the extracellular space. These findings demonstrate that HS biosynthesis has important regulatory effects on autophagy and that autophagy is critical for normal assembly of postsynaptic membrane specializations.
| S-EPMC5584867 | biostudies-literature