Induction of Osteogenic Differentiation by Hedgehog Proteins

Nakamura, Takashi; Aikawa, Tomonao; Iwamoto-Enomoto, Motomi; Iwamoto, Masahiro; Higuchi, Y.; Pacifici, Maurizio; Kinto, Naoki; Yamaguchi, Akira; Noji, Sumihare; Kurisu, Kojiro; Matsuya, Tokuzo

doi:10.1006/bbrc.1997.7156

Cited by 224 publications

(121 citation statements)

References 19 publications

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“…We tested next whether HS binding of the monomeric morphogen was required for Shh-dependent differentiation of C3H10T1/2 osteoblast precursor cells into AP-producing osteoblasts (30). AP-catalyzed paranitrophenylphosphate conversion into paranitrophenol measured at 405 nm served as a biological readout (Fig.…”

Section: Shhn and Shhnp Binding To Heparin Ismentioning

confidence: 99%

“…E18 HS disaccharide analysis revealed strongly increased levels of trisulfated disaccharide ⌬UA2S1,4GlcNS-6S (16.5% relative abundance in E18 HS versus 5.12% and 6.6% in E13 and E14 HS, respectively) despite only moderately increased overall sulfation (0.95 mol of sulfate/ disaccharide in E18 HS versus 0.7 and 0.8 mol in E13 and E14 HS, respectively) ( . To test this idea, we again quantified Shh-dependent differentiation of C3H10T1/2 osteoblast precursor cells (30) (Fig. 5A).…”

Section: Shhn and Shhnp Binding To Heparin Ismentioning

confidence: 99%

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Dual Roles of the Cardin-Weintraub Motif in Multimeric Sonic Hedgehog

Farshi¹,

Ohlig²,

Pickhinke³

et al. 2011

Journal of Biological Chemistry

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The fly morphogen Hedgehog (Hh) and its mammalian orthologs, Sonic, Indian, and Desert hedgehog, are secreted signaling molecules that mediate tissue patterning during embryogenesis and function in tissue homeostasis and regeneration in the adult. The function of all Hh family members is regulated at the levels of morphogen multimerization on the surface of producing cells, multimer release, multimer diffusion to target cells, and signal reception. These mechanisms are all known to depend on interactions of positively charged Hh amino acids (the Cardin-Weintraub (CW) motif) with negatively charged heparan sulfate (HS) glycosaminoglycan chains. However, a precise mechanistic understanding of these interactions is still lacking. The proteins of the Hh family are powerful morphogens that control growth and patterning of developing embryos. Current models for Hh activity suggest that the morphogen disperses from a localized source and forms a gradient that patterns fields of responsive cells expressing the Hh receptor Patched (Ptc).Genetic evidence suggests that this process critically depends on heparan sulfate proteoglycan (HSPG) 2 expression. Upon secretion to the cell surface, Drosophila Hh forms nanoscale oligomers on the cell surface that co-localize with HSPGs (1). HS binds to the Cardin-Weintraub (CW) motif found on all known Hhs and regulates their function in flies (2, 3) and mice (4). In Drosophila (5) as well as in mammalian cell culture (6, 7), Hhs are always released from producing cells in multimeric form, as demonstrated by gel filtration analysis of the soluble morphogen. Release of the multimeric morphogen (the processed Hh N-terminal signaling domain, designated HhNp) from the cell surface depends on the expression of Dispatched (8) and A disintegrin and metalloprotease (ADAM) family members that mediate ectodomain shedding from transfected Bosc23 cells (9). HS is involved in the formation of the HhNp extracellular gradient, which, in the fly, depends on the expression of the Drosophila Exostosin (Ext) family of proteins, encoded by the genes tout velu (ttv), brother of tout velu, and sister of tout velu and the glycosylphosphatidylinositollinked HSPGs Dally and Dally-like, corresponding to vertebrate glypicans (2, 3, 10). HS expression and Dally-like/glypican expression are also essential for signal reception and modulation on Ptc-expressing receiving cells (10 -14) and participate in HhNp-Ihog interaction (15). However, the essential role of direct morphogen-HSPG interactions in embryonic patterning was recently challenged (16). In that report, transgenic mice made deficient in two ShhNp CW amino acid residues implicated in HS binding (17) lacked an Shh-related phenotype, suggesting that direct morphogen-HS interactions were not essential for normal development. However, in that report as well as in others (16 -18), CW-dependent HS interactions were characterized using a recombinant, non-physiological monomeric morphogen termed ShhN, whereas embryogenesis depends entirely on the activity of morp...

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Section: Shhn and Shhnp Binding To Heparin Ismentioning

confidence: 99%

Section: Shhn and Shhnp Binding To Heparin Ismentioning

confidence: 99%

Dual Roles of the Cardin-Weintraub Motif in Multimeric Sonic Hedgehog

Farshi¹,

Ohlig²,

Pickhinke³

et al. 2011

Journal of Biological Chemistry

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“…A large proportion of Shh stimulated 10T1/2 cells enter the osteoblastic lineage, leading to a dramatic increase in alkaline phosphatase activity which can be readily assayed Nakamura et al, 1997;SpinellaJaegle et al, 2001). Studies in 10T1/2 cells have lead to a greater understanding of the functions of Shh (Pepinsky et al, 1998(Pepinsky et al, , 2000Williams et al, 1999;Saeki et al, 2000), Smo (Murone et al, 1999) and Gli family members (Ruiz i Altaba, 1999), as well as providing a means to investigate comparative effects of vertebrate Hh proteins (Pathi et al, 2001).…”

Section: Introductionmentioning

confidence: 99%

Novel genes regulated by Sonic Hedgehog in pluripotent mesenchymal cells

et al. 2002

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“…3D). Finally, we determined that the solubilized morphogens showed similar activities in the Shh-responsive cell line C3H10T1/2 (Nakamura et al, 1997), indicating that Gpc isoforms do not impact upon Shh biofunction in receiving cells (supplementary material Fig. S1).…”

Section: Loss Of Dally Function In Hh-producing Cells Affects Drosophmentioning

confidence: 97%

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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Induction of Osteogenic Differentiation by Hedgehog Proteins

Cited by 224 publications

References 19 publications

Dual Roles of the Cardin-Weintraub Motif in Multimeric Sonic Hedgehog

Dual Roles of the Cardin-Weintraub Motif in Multimeric Sonic Hedgehog

Novel genes regulated by Sonic Hedgehog in pluripotent mesenchymal cells

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

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