The transcription factor Foxc1 is necessary for Ihh–Gli2-regulated endochondral ossification

Yoshida, Michiko; Hata, Kenji; Takashima, Rikako; Ono, Kazuhisa; Nakamura, Eriko; Takahata, Yoshifumi; Murakami, Tomohiko; Iseki, Sachiko; Takano‐Yamamoto, Teruko; Nishimura, Riko; Yoneda, Toshiyuki

doi:10.1038/ncomms7653

Cited by 73 publications

(71 citation statements)

References 68 publications

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“…In addition, co-IP of the two proteins was also detected in BT549 cells, which possess high levels of both endogenous FOXC1 and Gli2 (Figure 4C). Consistent with our results, co-IP of FOXC1 and Gli2 has been recently reported in a study of endochondral ossification (Yoshida et al, 2015). …”

Section: Resultssupporting

confidence: 93%

FOXC1 Activates Smoothened-Independent Hedgehog Signaling in Basal-like Breast Cancer

et al. 2015

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Summary The mesoderm- and epithelial-mesenchymal transition-associated transcription factor FOXC1 is specifically overexpressed in basal-like breast cancer (BLBC), but its biochemical function is not understood. Here we demonstrate that FOXC1 controls cancer stem cell (CSC) properties enriched in BLBC cells via activation of Smoothened (SMO)-independent Hedgehog (Hh) signaling. This non-canonical activation of Hh is specifically mediated by Gli2. We further show that the N-terminal domain of FOXC1 (aa 1–68) binds directly to an internal region (aa 898–1168) of Gli2, enhancing the DNA-binding and transcription-activating capacity of Gli2. FOXC1 expression correlates with that of Gli2 and its targets in human breast cancers. Moreover, FOXC1 overexpression reduces sensitivity to anti-Hedgehog (Hh) inhibitors in BLBC cells and xenograft tumors. Together, these findings reveal FOXC1-mediated non-canonical Hh signaling that determines the BLBC stem-like phenotype and anti-Hh sensitivity, supporting inhibition of FOXC1 pathways as potential approaches for improving BLBC treatment.

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Section: Resultssupporting

confidence: 93%

FOXC1 Activates Smoothened-Independent Hedgehog Signaling in Basal-like Breast Cancer

et al. 2015

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“…Single heterozygotes are normal, but double heterozygotes exhibit many of the single-null mouse defects, indicating functional overlap between the two factors [126]. FOXC1 was proposed to interact with GLI2 in chondrocytes to stimulate the expression of IHH target genes, including Pthlh , Ptc1 , and Gli1 , and may also directly upregulate Col10a1 [127], but further studies are required to fully uncover the cell- and non-cell-autonomous actions of FOXC proteins in chondrogenesis.…”

Section: Helix-turn-helix Transcription Factorsmentioning

confidence: 99%

Transcriptional control of chondrocyte specification and differentiation

Liu

Samsa

Zhou

et al. 2017

Seminars in Cell & Developmental Biology

141

112

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A milestone in the evolutionary emergence of vertebrates was the invention of cartilage, a tissue that has key roles in modeling, protecting and complementing the bony skeleton. Cartilage is elaborated and maintained by chondrocytes. These cells derive from multipotent skeletal progenitors and they perform highly specialized functions as they proceed through sequential lineage commitment and differentiation steps. They form cartilage primordia, the primary skeleton of the embryo. They then transform these primordia either into cartilage growth plates, temporary drivers of skeletal elongation and endochondral ossification, or into permanent tissues, namely articular cartilage. Chondrocyte fate decisions and differentiated activities are controlled by numerous extrinsic and intrinsic cues, and they are implemented at the gene expression level by transcription factors. The latter are the focus of this review. Meritorious efforts from many research groups have led over the last two decades to the identification of dozens of key chondrogenic transcription factors. These regulators belong to all types of transcription factor families. Some have master roles at one or several differentiation steps. They include SOX9 and RUNX2/3. Others decisively assist or antagonize the activities of these masters. They include TWIST1, SOX5/6, and MEF2C/D. Many more have tissue-patterning roles and regulate cell survival, proliferation and the pace of cell differentiation. They include, but are not limited to, homeodomain-containing proteins and growth factor signaling mediators. We here review current knowledge of all these factors, one superclass, class, and family at a time. We then compile all knowledge into transcriptional networks. We also identify remaining gaps in knowledge and directions for future research to fill these gaps and thereby provide novel insights into cartilage disease mechanisms and treatment options.

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“…FoxC1 increased Col10a1 expression via direct binding to the Col10a1 gene promoter, and spontaneous Foxc1 mutant mice, called Ch mice, were completely devoid of Col10a1 -positive hypertrophic chondrocytes during sternal development. [48] In addition to Col10a1, the overexpression of FoxC1 in primary chondrocytes promoted the expression of PTHrP, a target gene of Ihh-Gli2 signaling in chondrocytes. FoxC1 physically associates with Gli2 and increases the DNA binding of Gli2 to Ihh target gene promoter.…”

Section: Chondrocyte Hypertrophymentioning

confidence: 99%

Transcriptional Network Controlling Endochondral Ossification

et al. 2017

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Endochondral ossification is the fundamental process of skeletal development in vertebrates. Chondrocytes undergo sequential steps of differentiation, including mesenchymal condensation, proliferation, hypertrophy, and mineralization. These steps, which are required for the morphological and functional changes in differentiating chondrocytes, are strictly regulated by a complex transcriptional network. Biochemical and mice genetic studies identified chondrogenic transcription factors critical for endochondral ossification. The transcription factor sex-determining region Y (SRY)-box 9 (Sox9) is essential for early chondrogenesis, and impaired Sox9 function causes severe chondrodysplasia in humans and mice. In addition, recent genome-wide chromatin immunoprecipitation-sequencing studies revealed the precise regulatory mechanism of Sox9 during early chondrogenesis. Runt-related transcription factor 2 promotes chondrocyte hypertrophy and terminal differentiation. Interestingly, endoplasmic reticulum (ER) stress-related transcription factors have recently emerged as novel regulators of chondrocyte differentiation. Here we review the transcriptional mechanisms that regulate endochondral ossification, with a focus on Sox9.

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The transcription factor Foxc1 is necessary for Ihh–Gli2-regulated endochondral ossification

Cited by 73 publications

References 68 publications

FOXC1 Activates Smoothened-Independent Hedgehog Signaling in Basal-like Breast Cancer

FOXC1 Activates Smoothened-Independent Hedgehog Signaling in Basal-like Breast Cancer

Transcriptional control of chondrocyte specification and differentiation

Transcriptional Network Controlling Endochondral Ossification

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