The Balance of WNT and FGF Signaling Influences Mesenchymal Stem Cell Fate During Skeletal Development

Maruyama, Takamitsu; Mirando, Anthony J.; Deng, Chu‐Xia; Hsu, Wei-Hsuan

doi:10.1126/scisignal.2000727

Cited by 111 publications

(160 citation statements)

References 53 publications

Supporting

Mentioning

151

Contrasting

Order By: Relevance

“…Regulation of Wnt signaling by FGF and Sox2. The Wnt pathway plays important roles in osteoblast and bone development and is generally considered to be a prodifferentiation signal in osteoblasts and an overall anabolic signal in bone tissue (16,21,28,43). Our previous studies of the antagonistic effect of FGF on osteoblast differentiation and on the Wnt prodifferentiation pathway had identified multiple mechanisms by which FGF signaling inhibited Wnt-induced transcription in osteoblasts.…”

Section: Discussionmentioning

confidence: 99%

Distinct Functions of Sox2 Control Self-Renewal and Differentiation in the Osteoblast Lineage

Seo

Basu-Roy

Zavadil

et al. 2011

Molecular and Cellular Biology

View full text Add to dashboard Cite

The transcription factor Sox2 is a key player in the maintenance of pluripotency and "stemness. To form bone, fat, muscle, and cartilage, multipotent mesenchymal stem cells (MSCs) must commit to a specific cell lineage and then undergo a sequential program of proliferation and differentiation. Primitive osteoprogenitors are thought to arise from multipotent MSCs that commit to and then differentiate into preosteoblast and mature bone-forming osteoblasts (4, 41). Signaling networks of fibroblast growth factors (FGFs), bone morphogenetic proteins (BMPs), Indian Hedgehog homolog (IHH), Wnt, and Notch orchestrate this complex process (20,23), and the transcription factors Runx2 and Osterix (OSX) are essential for formation of the osteoblastic lineage (22, 32). However, little is known about other factors that regulate early cell fate decisions and the mechanisms that determine the balance between self-renewal and differentiation of osteoprogenitor cells (20).We recently reported that the transcription factor Sox2 is essential for the self-renewal and proliferation of osteoblast precursors. Conditional knockout (cko) of the Sox2 gene in the osteoblastic lineage generates mice that, although mosaic with respect to Sox2 inactivation, are strongly osteopenic, and Sox2 inactivation in cultured primary osteoblasts has been shown to cause exhaustion of their proliferative ability and induction of senescence (6). Sox2 expression is highly enriched in a small subset of primary osteoblasts that form nonadherent spheres that are thought to represent a stem-like population (6). These findings suggested that Sox2 marks and maintains a population of multipotent or unipotent osteoblast stem cells that is responsible for self-renewal of the osteoblast lineage.Sox2, a member of the Sox HMG box family of transcription factors, is required early in embryonic development to maintain pluripotency and self-renewal in embryonic stem (ES) cells (37). Sox2 is a maternally transmitted factor that is first expressed in the cells of the inner cell mass of the blastocyst. In the developing embryo, Sox2 expression is extinguished in most tissues, but it remains strongly expressed in stem cells of the central nervous system (CNS), retina, and the primordial gut (40,42,50) and plays an essential role in the maintenance of undifferentiated lineage progenitors such as neural stem cells (15,40). It is also a critical reprogramming factor for the conversion of somatic cells to induced pluripotent stem cells (iPSC) (48).In the osteoblast lineage, Sox2 is expressed at relatively low levels in immature cells, both in vitro and in vivo, and is induced by FGF signaling that stimulates proliferation of preosteoblasts and inhibits their differentiation (25). Constitutive expression of Sox2 can increase sphere formation and by itself can inhibit osteoblast differentiation. Sox2 also participates in the inhibitory effect of FGF on the prodifferentiation Wnt pathway by binding to ␤-catenin, a major effector of canonical Wnt signaling, and inhibiting its transcr...

show abstract

Section: Discussionmentioning

confidence: 99%

Distinct Functions of Sox2 Control Self-Renewal and Differentiation in the Osteoblast Lineage

Seo

Basu-Roy

Zavadil

et al. 2011

Molecular and Cellular Biology

View full text Add to dashboard Cite

show abstract

“…During cranial suture development, WNT/β-catenin signaling controls stem cell renewal, proliferation, and lineage specification by balancing the activity of the FGF and BMP signaling pathways (Maruyama et al 2010). Mechanistically, WNT/β-catenin signaling induces Fgf18 expression through induction of a complex with RUNX2 and TCF/LEF transcription factors on the Fgf18 promoter ( Fig.…”

Section: Intramembranous Mesenchymal Condensationsmentioning

confidence: 99%

Fibroblast growth factor signaling in skeletal development and disease

2015

View full text Add to dashboard Cite

Fibroblast growth factor (FGF) signaling pathways are essential regulators of vertebrate skeletal development. FGF signaling regulates development of the limb bud and formation of the mesenchymal condensation and has key roles in regulating chondrogenesis, osteogenesis, and bone and mineral homeostasis. This review updates our review on FGFs in skeletal development published in Genes & Development in 2002, examines progress made on understanding the functions of the FGF signaling pathway during critical stages of skeletogenesis, and explores the mechanisms by which mutations in FGF signaling molecules cause skeletal malformations in humans. Links between FGF signaling pathways and other interacting pathways that are critical for skeletal development and could be exploited to treat genetic diseases and repair bone are also explored.

show abstract

“…Moreover, our data interpretation also provides some evidence that lower levels of IGF1 (<50 CPM reads) might combine with other growth factors, which have previously been associated to the development of SSC. Indeed, the interplay between IGF1 and Wnt or Fgf signaling pathways has been suggested to contribute to the pathogenesis of craniosynostosis (ten Berge et al, 2008;Behr et al, 2010;Maruyama et al, 2010). For example, a number of mutations, including in the FGFR3, TGFBR1 and TGFB3 genes, have been associated with syndromic forms of the disease (Passos-Bueno et al, 2008;Cunningham et al, 2011).…”

Section: −4mentioning

confidence: 99%

Activation of the IGF1 pathway mediates changes in cellular contractility and motility in single-suture craniosynostosis

Al-Rekabi

Wheeler

Leonard

et al. 2016

Journal of Cell Science

View full text Add to dashboard Cite

Insulin growth factor 1 (IGF1) is a major anabolic signal that is essential during skeletal development, cellular adhesion and migration. Recent transcriptomic studies have shown that there is an upregulation in IGF1 expression in calvarial osteoblasts derived from patients with singlesuture craniosynostosis (SSC). Upregulation of the IGF1 signaling pathway is known to induce increased expression of a set of osteogenic markers that previously have been shown to be correlated with contractility and migration. Although the IGF1 signaling pathway has been implicated in SSC, a correlation between IGF1, contractility and migration has not yet been investigated. Here, we examined the effect of IGF1 activation in inducing cellular contractility and migration in SSC osteoblasts using micropost arrays and time-lapse microscopy. We observed that the contractile forces and migration speeds of SSC osteoblasts correlated with IGF1 expression. Moreover, both contractility and migration of SSC osteoblasts were directly affected by the interaction of IGF1 with IGF1 receptor (IGF1R). Our results suggest that IGF1 activity can provide valuable insight for phenotype-genotype correlation in SSC osteoblasts and might provide a target for therapeutic intervention.

show abstract

The Balance of WNT and FGF Signaling Influences Mesenchymal Stem Cell Fate During Skeletal Development

Cited by 111 publications

References 53 publications

Distinct Functions of Sox2 Control Self-Renewal and Differentiation in the Osteoblast Lineage

Distinct Functions of Sox2 Control Self-Renewal and Differentiation in the Osteoblast Lineage

Fibroblast growth factor signaling in skeletal development and disease

Activation of the IGF1 pathway mediates changes in cellular contractility and motility in single-suture craniosynostosis

Contact Info

Product

Resources

About