Interaction of LEF1 with TAZ is necessary for the osteoblastogenic activity of Wnt3a

Jumpei Kida,Kenji Hata,Eriko Nakamura,Yoshinobu Maeda,Hiroko Yagi,Yoshifumi Takahata,Riko Nishimura,Tomohiko Murakami

doi:10.1038/s41598-018-28711-4

Jumpei Kida, Kenji Hata + Show 6 more

Open Access

https://doi.org/10.1038/s41598-018-28711-4

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Journal: Scientific Reports	Publication Date: Jul 10, 2018
Citations: 7	License type: open-access

Affiliation: Osaka University

Abstract

Canonical Wnt signalling plays an important role in osteoblast differentiation and bone formation. However, the molecular mechanisms by which canonical Wnt signalling exerts its osteoblastogenic effect remain elusive. Here, we investigated the relationship between lymphoid enhancer-binding factor 1 (LEF1) and transcriptional co-activator with PDZ-binding motif (TAZ), both of which are transcriptional regulators that mediate canonical Wnt signalling during osteoblast differentiation. Reporter assay and co-immunoprecipitation experiments revealed functional and physical interaction between LEF1 and TAZ. Overexpression of dominant-negative forms of either LEF1 or TAZ markedly inhibited Wnt3a-dependent osteoblast differentiation. Moreover, we found that LEF1 and TAZ formed a transcriptional complex with runt-related transcription factor 2 (Runx2) and that inhibition of LEF1 or TAZ by their dominant-negative forms dramatically suppressed the osteoblastogenic activity of Ruxn2. Additionally, Wnt3a enhanced osteoblast differentiation induced by bone morphogenetic protein 2 (BMP2), which stimulates osteoblast differentiation by regulating Runx2. Collectively, these findings suggest that interaction between LEF1 and TAZ is crucial for the osteoblastogenic activity of Wnt3a and that LEF1 and TAZ contribute to the cooperative effect of Wnt3a and BMP2 on osteoblast differentiation through association with Runx2.

Highlights

Bone metabolism is an important aspect of skeletal development, homeostasis of serum calcium and phosphate levels, and maintenance of haematopoiesis[1,2]
These findings suggest that interaction between lymphoid enhancer-binding factor 1 (LEF1) and transcriptional coactivator with PDZ-binding motif (TAZ) is crucial for the osteoblastogenic activity of Wnt3a and that LEF1 and TAZ contribute to the cooperative effect of Wnt3a and bone morphogenetic protein 2 (BMP2) on osteoblast differentiation through association with Runx[2]
We found that interaction between LEF1 and TAZ is necessary for the osteoblastogenic activity of Wnt3a, a well-known canonical Wnt family member[6,21,22,23]

Summary

Introduction

Bone metabolism is an important aspect of skeletal development, homeostasis of serum calcium and phosphate levels, and maintenance of haematopoiesis[1,2]. Canonical Wnt signalling stimulates bone formation and osteoblast differentiation[6,7]. The binding of Wnt to its receptor complex stabilises β-catenin against ubiquitin-proteasome degradation, enabling it to translocate into the nucleus to regulate the expression of target genes by interacting with the transcription factor lymphoid enhancer-binding factor 1 (LEF1)[5]. Wnt stabilises TAZ as well as β-catenin and stimulates translocation of TAZ into the nucleus, which promotes osteoblast differentiation[16] Consistent with these findings, TAZ interacts with Runx[2] and stimulates bone formation[18,19]. To further understand the molecular mechanism by which canonical Wnt signalling stimulates osteoblast differentiation of mesenchymal cells, we examined the roles of LEF1 and TAZ in osteoblast differentiation. Our findings provide a novel paradigm for the molecular mechanism of canonical Wnt signalling during osteoblast differentiation of mesenchymal cells

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Conclusion