Sulfotransferase Ndst1 is Needed for Mandibular and TMJ Development

Yasuda, Tadashi; Mundy, Christina; Kinumatsu, Takashi; Shibukawa, Yoshihiro; Sendo, Toshiaki; Grobe, Kay; Minugh-Purvis, Nancy; Pacifici, Maurizio; Koyama, Eiki

doi:10.1177/0022034510373766

Cited by 30 publications

(29 citation statements)

References 37 publications

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“…Although none of the authors characterised teeth of the Ext1 or Ext2- mutant mice, dental defect were described in Ndst1- null mice [30]. NDST1 is an enzyme that acts downstream of EXTs in the biosynthesis of heparan sulphate.…”

Section: Discussionmentioning

confidence: 99%

HSPG-Deficient Zebrafish Uncovers Dental Aspect of Multiple Osteochondromas

et al. 2012

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Multiple Osteochondromas (MO; previously known as multiple hereditary exostosis) is an autosomal dominant genetic condition that is characterized by the formation of cartilaginous bone tumours (osteochondromas) at multiple sites in the skeleton, secondary bursa formation and impingement of nerves, tendons and vessels, bone curving, and short stature. MO is also known to be associated with arthritis, general pain, scarring and occasional malignant transformation of osteochondroma into secondary peripheral chondrosarcoma. MO patients present additional complains but the relevance of those in relation to the syndromal background needs validation. Mutations in two enzymes that are required during heparan sulphate synthesis (EXT1 or EXT2) are known to cause MO. Previously, we have used zebrafish which harbour mutations in ext2 as a model for MO and shown that ext2−/− fish have skeletal defects that resemble those seen in osteochondromas. Here we analyse dental defects present in ext2−/− fish. Histological analysis reveals that ext2−/− fish have very severe defects associated with the formation and the morphology of teeth. At 5 days post fertilization 100% of ext2−/− fish have a single tooth at the end of the 5th pharyngeal arch, whereas wild-type fish develop three teeth, located in the middle of the pharyngeal arch. ext2−/− teeth have abnormal morphology (they were shorter and thicker than in the WT) and patchy ossification at the tooth base. Deformities such as split crowns and enamel lesions were found in 20% of ext2+/− adults. The tooth morphology in ext2−/− was partially rescued by FGF8 administered locally (bead implants). Our findings from zebrafish model were validated in a dental survey that was conducted with assistance of the MHE Research Foundation. The presence of the malformed and/or displaced teeth with abnormal enamel was declared by half of the respondents indicating that MO might indeed be also associated with dental problems.

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Section: Discussionmentioning

confidence: 99%

HSPG-Deficient Zebrafish Uncovers Dental Aspect of Multiple Osteochondromas

et al. 2012

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“…Growth plate and skeletal aberrations were also observed in mutant mice of HS modifying genes such as 6-O-sulfotransferase-1 and N-sulfotransferase 1 . Ablation of Perlecan or Glypican-3 genes, both of which encode HSPG core proteins and are expressed in the growth plate, also results in growth plate and skeletal abnormalities (Arikawa-Hirasawa et al, 1999; Habuchi et al, 2007; Viviano et al, 2005; Yasuda et al, 2010). These observations suggest that HS-dependent mechanisms are major regulators of skeletogenesis and growth plate function, but far less is known about whether similar mechanisms operate in perichondrium to regulate its phenotype and roles.…”

Section: Introductionmentioning

confidence: 99%

Perichondrium phenotype and border function are regulated by Ext1 and heparan sulfate in developing long bones: A mechanism likely deranged in Hereditary Multiple Exostoses

Huegel

Mundy

Sgariglia

et al. 2013

Developmental Biology

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During limb skeletogenesis the cartilaginous long bone anlagen and their growth plates become delimited by perichondrium with which they interact functionally. Yet, little is known about how, despite being so intimately associated with cartilage, perichondrium acquires and maintains its distinct phenotype and exerts its border function. Because perichondrium becomes deranged and interrupted by cartilaginous outgrowths in Hereditary Multiple Exostoses (HME), a pediatric disorder caused by EXT mutations and consequent heparan sulfate (HS) deficiency, we asked whether EXT genes and HS normally have roles in establishing its phenotype and function. Indeed, conditional Ext1 ablation in perichondrium and lateral chondrocytes flanking the epiphyseal region of mouse embryo long bone anlagen – a region encompassing the groove of Ranvier – caused ectopic cartilage formation. A similar response was observed when HS function was disrupted in long bone anlagen explants by genetic, pharmacological or enzymatic means, a response preceded by ectopic BMP signaling within perichondrium. These treatments also triggered excess chondrogenesis and cartilage nodule formation and overexpression of chondrogenic and matrix genes in limb bud mesenchymal cells in micromass culture. Interestingly, the treatments disrupted the peripheral definition and border of the cartilage nodules in such a way that many nodules overgrew and fused with each other into large amorphous cartilaginous masses. Interference with HS function reduced the physical association and interactions of BMP2 with HS and increased the cell responsiveness to endogenous and exogenous BMP proteins. In sum, Ext genes and HS are needed to establish and maintain perichondrium’s phenotype and border function, restrain pro-chondrogenic signaling proteins including BMPs, and restrict chondrogenesis. Alterations in these mechanisms may contribute to exostosis formation in HME, particularly at the expense of regions rich in progenitor cells including the groove of Ranvier.

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“…Eagle's medium (DMEM), and we incubated the soluble proteins with pooled glycosaminoglycans isolated from E12.5-E18 mouse embryos (EHS). EHS was used because of its essential role in Hh signaling in vivo (Grobe et al, 2005;Pallerla et al, 2007;Yasuda et al, 2010). After EHS-conditioned media were incubated for 0-3 h at 37°C to allow for protease-substrate assembly and Shh processing, samples were precipitated with trichloroacetic acid (TCA) and analyzed by SDS-PAGE and immunoblotting as described above.…”

Section: Heparan Sulfate Potentiates Shh Processingmentioning

confidence: 99%

Sonic hedgehog processing and release are regulated by glypican heparan sulfate proteoglycans

Ortmann,

Pickhinke,

Exner

et al. 2015

Journal of Cell Science

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There was an error published in J. Cell Sci. 128, 2374-2385.The reference Oustah et al. (2014) was cited incorrectly throughout the manuscript and in the reference list. Citations of Oustah et al. (2014) should read Al Oustah et al. (2014), and the correct reference is given below.Al Oustah, A., Danesin, C., Khouri-Farah, N., Farreny, M.-A., Escalas, N., Cochard, P., Glise, B. and Soula, C. (2014 show that glypican heparan sulfate proteoglycans regulate this process, through their heparan sulfate chains, in a cell autonomous manner. Heparan sulfate specifically modifies Shh processing at the cell surface, and purified glycosaminoglycans enhance the proteolytic removal of N-and C-terminal Shh peptides under cellfree conditions. The most likely explanation for these observations is direct Shh processing in the extracellular compartment, suggesting that heparan sulfate acts as a scaffold or activator for Shh ligands and the factors required for their turnover. We also show that purified heparan sulfate isolated from specific cell types and tissues mediates the release of bioactive Shh from pancreatic cancer cells, revealing a previously unknown regulatory role for these versatile molecules in a pathological context.

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Sulfotransferase Ndst1 is Needed for Mandibular and TMJ Development

Cited by 30 publications

References 37 publications

HSPG-Deficient Zebrafish Uncovers Dental Aspect of Multiple Osteochondromas

HSPG-Deficient Zebrafish Uncovers Dental Aspect of Multiple Osteochondromas

Perichondrium phenotype and border function are regulated by Ext1 and heparan sulfate in developing long bones: A mechanism likely deranged in Hereditary Multiple Exostoses

Sonic hedgehog processing and release are regulated by glypican heparan sulfate proteoglycans

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