Wnt-dependent activation of ERK mediates repression of chondrocyte fate during calvarial development

Ibarra, Beatriz; Machen, Cody; Atit, Radhika

doi:10.1101/2021.04.23.441148

2021

DOI: 10.1101/2021.04.23.441148

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Wnt-dependent activation of ERK mediates repression of chondrocyte fate during calvarial development

Beatriz Ibarra

Cody Machen

Radhika Atit

Abstract: Wnt signaling regulates cell fate decisions in diverse contexts during development, and loss of Wnt signaling in the cranial mesenchyme results in a robust and binary cell fate switch from cranial bone to ectopic cartilage. The Extracellular signal-regulated protein kinase 1 and 2 (ERK1/2) and Wnt signaling pathways are activated during calvarial osteoblast cell fate selection. Here, we test the hypothesis that ERK signaling is a mediator of Wnt-dependent cell fate decisions in the cranial mesenchyme. First, w… Show more

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Cited by 4 publications

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“…Role of Wnt in cell fate specificationWnt signaling regulates cell fate decisions in diverse contexts during development, and loss of Wnt signaling in the cranial mesenchyme results in a robust and binary cell fate switch from cranial bone to ectopic cartilage. Genetic interaction between the Wnt and ERK signaling pathways to repress Sox9 and ERK signaling is activated downstream of Wnt signaling during calvarial osteoblast fate decisions in vivo(Ibarra et al, 2021) …”

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confidence: 99%

Wnt signaling pathway: A comprehensive review

Hayat

Manzoor

Hussain

2022

Cell Biology International

119

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Wnt signaling is an evolutionary cell‐to‐cell coordination mechanism and it is highly critical for a variety of physiological processes of an organism's body, including stem cell regeneration, proliferation, division, migration, polarity of a cell, determining fate of the cell and specification of neural crest, neural symmetry and morphogenesis. Wnts are extracellular secreted glycol proteins, consisted of a family of 19 human proteins that represent the complex nature of the regulatory structure and physiological efficiency of signaling. Moreover, a Wnt/β‐catenin‐dependent pathway and the β‐catenin‐independent pathway that is further classified into the Planar Cell Polarity and Wnt/Ca2+ pathways have been established as key signaling nodes downstream of the frizzled (Fz/Fzd) receptor, and these nodes are extensively analyzed at biochemical and molecular levels. Genetic and epigenetic activities that ultimately characterize the pathway and its subsequent responses contribute to Wnt‐β‐catenin signaling pathway hypo or hyper‐activation and is associated with the variety of human disorders progression most significantly cancers. Recognizing how this mechanism operates is crucial to the advancement of cancer prevention therapies or regenerative medicine methods.

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confidence: 99%

Wnt signaling pathway: A comprehensive review

Hayat

Manzoor

Hussain

2022

Cell Biology International

119

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Wnt/β-Catenin Signaling Inhibits Osteogenic Differentiation in Human Periodontal Ligament Fibroblasts

Iizumi

Honda

2022

Biomimetics

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The periodontal ligament is a collagenous tissue that is important for maintaining the homeostasis of cementum and alveolar bone. In tendon cells, Wnt/β-catenin signaling has been reported to regulate the expression level of Scleraxis (Scx) and Mohawk Homeobox (Mkx) gene and maintain the tissue homeostasis, while its role in the periodontal ligament is unclear. The aim of this study was to investigate the effects of Wnt/β-catenin signaling induced by Wnt-3a stimulation on the inhibition of osteogenic differentiation of human periodontal ligament fibroblasts (HPLFs). During osteogenic differentiation of HPLFs, they formed bone nodules independently of alkaline phosphatase (ALP) activity. After stimulation of Wnt-3a, the expression of β-catenin increased, and nuclear translocation of β-catenin was observed. These data indicate that Wnt-3a activated Wnt/β-catenin signaling. Furthermore, the stimulation of Wnt-3a inhibited the bone nodule formation and suppressed the expression of osteogenic differentiation-related genes such as Runx2, Osteopontin and Osteocalcin, and upregulated the gene expression of Type-I collagen and Periostin (Postn). Scx may be involved in the suppression of osteogenic differentiation in HPLFs. In conclusion, Wnt/β-catenin signaling may be an important signaling pathway that inhibits the osteogenic differentiation in HPLFs by the upregulation of Scx gene expression and downregulation of osteogenic differentiation-related genes.

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Modulation of miR-204 Expression during Chondrogenesis

Carbonare

Bertacco

Minoia

et al. 2022

IJMS

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RUNX2 and SOX9 are two pivotal transcriptional regulators of chondrogenesis. It has been demonstrated that RUNX2 and SOX9 physically interact; RUNX2 transactivation may be inhibited by SOX9. In addition, RUNX2 exerts reciprocal inhibition on SOX9 transactivity. Epigenetic control of gene expression plays a major role in the alternative differentiation fates of stem cells; in particular, it has been reported that SOX9 can promote the expression of miRNA (miR)-204. Our aim was therefore to investigate the miR-204-5p role during chondrogenesis and to identify the relationship between this miR and the transcription factors plus downstream genes involved in chondrogenic commitment and differentiation. To evaluate the role of miR-204 in chondrogenesis, we performed in vitro transfection experiments by using Mesenchymal Stem Cells (MSCs). We also evaluated miR-204-5p expression in zebrafish models (adults and larvae). By silencing miR-204 during the early differentiation phase, we observed the upregulation of SOX9 and chondrogenic related genes compared to controls. In addition, we observed the upregulation of COL1A1 (a RUNX2 downstream gene), whereas RUNX2 expression of RUNX2 was slightly affected compared to controls. However, RUNX2 protein levels increased in miR-204-silenced cells. The positive effects of miR204 silencing on osteogenic differentiation were also observed in the intermediate phase of osteogenic differentiation. On the contrary, chondrocytes’ maturation was considerably affected by miR-204 downregulation. In conclusion, our results suggest that miR-204 negatively regulates the osteochondrogenic commitment of MSCs, while it positively regulates chondrocytes’ maturation.

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Wnt-dependent activation of ERK mediates repression of chondrocyte fate during calvarial development

Cited by 4 publications

References 57 publications

Wnt signaling pathway: A comprehensive review

Wnt signaling pathway: A comprehensive review

Wnt/β-Catenin Signaling Inhibits Osteogenic Differentiation in Human Periodontal Ligament Fibroblasts

Modulation of miR-204 Expression during Chondrogenesis

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