Regulation of <i>Sox9</i> by Sonic Hedgehog (<i>Shh</i>) is essential for patterning and formation of tracheal cartilage

Park, Jinhyung; Zhang, Jennifer J. R.; Moro, Anne; Kushida, Michelle; Wegner, Michael; Kim, Peter C.W.

doi:10.1002/dvdy.22192

Cited by 84 publications

(97 citation statements)

References 49 publications

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“…We analyzed the expression of SRY (sex-determining region Y)-box 9 (SOX9), a master regulator of chondrogenesis essential for patterning and formation of the tracheal cartilage (Park et al, 2010). In E14.5 controls, the segmented SOX9 expression showed the pattern of the future cartilage rings.…”

Section: Mek1 Epithelial Inactivation On a Mek2 Null Background Resulmentioning

confidence: 99%

Crucial requirement of ERK/MAPK signaling in respiratory tract development

et al. 2014

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There was an error published in Development 141, 3197-3211.In the key for Fig. 3C, the grey bars were labelled with the incorrect genotype name. The correct genotype is Mek1 +/flox ;Mek2+/cre . This error does not affect the conclusions of the paper.The authors apologise to readers for this mistake. In vitro, the loss of Mek function in lung mesenchyme did not interfere with lung growth and branching, suggesting that both the reduced intrathoracic space due to the dysmorphic rib cage and the omphalocele impaired lung development in vivo. Conversely, Mek mutation in the respiratory epithelium caused lung agenesis, a phenotype resulting from the direct impact of the ERK/MAPK pathway on cell proliferation and survival. No tracheal epithelial cell differentiation occurred and no SOX2-positive progenitor cells were detected in mutants, implying a role for the ERK/MAPK pathway in trachea progenitor cell maintenance and differentiation. Moreover, these anomalies were phenocopied when the Erk1 and Erk2 genes were mutated in airway epithelium. Thus, the ERK/MAPK pathway is required for the integration of mesenchymal and epithelial signals essential for the development of the entire respiratory tract.

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Section: Mek1 Epithelial Inactivation On a Mek2 Null Background Resulmentioning

confidence: 99%

Crucial requirement of ERK/MAPK signaling in respiratory tract development

et al. 2014

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“…These results show that a 50% reduction of Sox9 already leads to a lethal phenotype in humans and mice. In mice lacking sonic hedgehog, the level of Sox9 is almost absent at the time of chondrogenesis, resulting in the failure of tracheal cartilage formation (34). The reduced percentage of Sox9 in Ca v 3.2 −/− trachea (Fig.…”

Section: Discussionmentioning

confidence: 96%

“…A certain level of Sox9 expression is essential for the condensation of chondroprogenitor cells into segments along developing trachea at E14.5 (14,34). Sox9-positive cells formed a clear banding pattern on the ventral side of developing trachea in WT but not Ca v 3.2 −/− mice (Fig.…”

Section: Ca V 32 Enhances Chondrogenesis In a Calcineurin/nfat-depenmentioning

confidence: 93%

Ca _v 3.2 T-type calcium channel is required for the NFAT-dependent Sox9 expression in tracheal cartilage

Lin

Tzeng

Lee

et al. 2014

Proc. Natl. Acad. Sci. U.S.A.

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Significance The tracheal cartilage rings are important for protecting and maintaining the airway. However, the chondrogenesis of tracheal cartilage is not completely understood. We demonstrate that the Ca v 3.2 T-type calcium channel is required for normal tracheal cartilage ring formation. Calcium influx via Ca v 3.2 induces chondrogenesis and up-regulates a chondrogenic master gene, sex determination region of Y chromosome (SRY)-related high-mobility group-Box gene 9 (Sox9), via a calcium and calcineurin-dependent pathway. Ca v 3.2-dependent regulation of Sox9 is mediated by a newly identified nuclear factor of activated T-cell binding site on the Sox9 promoter. Our study provides novel insight into the roles of Ca v 3.2 T-type calcium channels in tracheal development. Moreover, CACNA1H , the human homolog of the mouse Ca v 3.2-encoding gene, may be a potential candidate gene involved in congenital tracheal stenosis in humans.

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“…6) Shh mice indicated that Shh signaling is a key determinant in cartilage development. 25) Furthermore, cyclopamine, which is a steroidal alkaloid derived from plants, can block Shh signaling by inhibition of smoothened, [26][27][28] preventing atractylenolide from positively regulating Gli promoter activity, chondrogenic markers and Sox9 expression. These results demonstrated that the effects of atractylenolide on chondrogenic differentiation in MSCs are dependent on Shh signaling.…”

Section: Discussionmentioning

confidence: 99%

Targeting of the Sonic Hedgehog Pathway by Atractylenolides Promotes Chondrogenic Differentiation of Mesenchymal Stem Cells

Wei

Wang

et al. 2012

Biological & Pharmaceutical Bulletin

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Molecules that enhance chondrogenic differentiation in mesenchymal stem cells (MSCs) were identified and isolated using an in vitro Gli reporter gene assay in MSCs incorporating a Sonic Hedgehog (Shh) target. Atractylenolide III, which promoted Gli1-mediated transcriptional activity, was isolated from an ethyl acetate extract of the Rhizoma, Atractylodis macrocephalae. After dehydration, atractylenolide III was transformed to atractylenolide I. Both atractylenolides were confirmed by MS, UV, IR, 1 H-and 13 C-NMR spectra. Atractylenolide III (which contains -OH at the 8-position) and atractylenolide I (which lacks -OH at the 8-position) were found to effectively promote the activity of the Gli promoter. While the hydroxyl group of atractylenolide III was not essential for the effect of atractylenolide, its effect was dependent on Shh signaling. Phenotypic cellular analysis indicated that atractylenolides induced MSCs to differentiate into chondrocytes, as shown by increased expression of specific chondrogenic markers including collagen II, aggrecan and the cartilage related transcription factor, Sox9. Atractylenolides significantly increased the expression of Shh and its target gene Gli-1, indicating that Shh signaling was activated by atractylenolides. Moreover, inhibition of Shh signaling reduced the effect of atractylenolides on the chondrogenic phenotype. The discovery that atractylenolides induce chondrocytes from MSCs is promising for bony disease therapy.

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Regulation of Sox9 by Sonic Hedgehog (Shh) is essential for patterning and formation of tracheal cartilage

Cited by 84 publications

References 49 publications

Crucial requirement of ERK/MAPK signaling in respiratory tract development

Crucial requirement of ERK/MAPK signaling in respiratory tract development

Ca _v 3.2 T-type calcium channel is required for the NFAT-dependent Sox9 expression in tracheal cartilage

Targeting of the Sonic Hedgehog Pathway by Atractylenolides Promotes Chondrogenic Differentiation of Mesenchymal Stem Cells

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Regulation of Sox9 by Sonic Hedgehog (Shh) is essential for patterning and formation of tracheal cartilage

Cited by 84 publications

References 49 publications

Crucial requirement of ERK/MAPK signaling in respiratory tract development

Crucial requirement of ERK/MAPK signaling in respiratory tract development

Ca v 3.2 T-type calcium channel is required for the NFAT-dependent Sox9 expression in tracheal cartilage

Targeting of the Sonic Hedgehog Pathway by Atractylenolides Promotes Chondrogenic Differentiation of Mesenchymal Stem Cells

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Ca _v 3.2 T-type calcium channel is required for the NFAT-dependent Sox9 expression in tracheal cartilage