Augmentation of smad-dependent BMP signaling in neural crest cells causes craniosynostosis in mice

Komatsu, Yoshihiro; Yu, Paul B.; Kamiya, Nobuhiro; Pan, Haichun; Fukuda, T.; Scott, Gregory J.; Ray, Manas K.; Yamamura, Ken Ichi; Mishina, Yuji

doi:10.1002/jbmr.1857

Cited by 89 publications

(115 citation statements)

References 55 publications

(110 reference statements)

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“…Point mutations within the NOGGIN (NOG) gene cause reduced binding capacity to BMP ligands and result in reduced sequestration of BMP ligand by the mutant protein, which shifts the state of the BMP signaling pathway balance toward activation (Lehmann et al 2007) and results in disruption of digit patterning. (Komatsu et al 2013). During calvarial development, a major role of FGF is to suppress expression of the BMP inhibitor noggin via Erk1 and Erk2 MAPK signaling and thus induce suture closure by increasing BMP signaling (Warren et al 2003).…”

Section: Digit Malformations Caused By Disruption Of Tgf-b and Bmp Simentioning

confidence: 99%

TGF-β Family Signaling in Connective Tissue and Skeletal Diseases

MacFarlane

Haupt

Dietz

et al. 2017

Cold Spring Harb Perspect Biol

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The transforming growth factor b (TGF-b) family of signaling molecules, which includes TGF-bs, activins, inhibins, and numerous bone morphogenetic proteins (BMPs) and growth and differentiation factors (GDFs), has important functions in all cells and tissues, including soft connective tissues and the skeleton. Specific TGF-b family members play different roles in these tissues, and their activities are often balanced with those of other TGF-b family members and by interactions with other signaling pathways. Perturbations in TGF-b family pathways are associated with numerous human diseases with prominent involvement of the skeletal and cardiovascular systems. This review focuses on the role of this family of signaling molecules in the pathologies of connective tissues that manifest in rare genetic syndromes (e.g., syndromic presentations of thoracic aortic aneurysm), as well as in more common disorders (e.g., osteoarthritis and osteoporosis). Many of these diseases are caused by or result in pathological alterations of the complex relationship between the TGF-b family of signaling mediators and the extracellular matrix in connective tissues.T he transforming growth factor b (TGF-b) family of cytokines comprises the three TGF-b proteins (TGF-b1, TGF-b2, and TGFb3) and related growth and differentiation factors such as activins, inhibins, bone morphogenic proteins (BMPs), and growth and differentiation factors (GDFs). These molecules play critical roles both in normal development and in several pathological conditions, including inflammation, fibrosis, and cancer (reviewed in Li and Flavell 2006;Gordon and Blobe 2008;Ikushima and Miyazono 2010). This review focuses on the role of these proteins in development and homeostasis of the skeleton and other connective tissues (summarized in Fig. 1) and on the diseases that ensue when these pathways are altered. Aberrant signaling in these pathways has been associated with common connective 6 These authors contributed equally to this work.

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Section: Digit Malformations Caused By Disruption Of Tgf-b and Bmp Simentioning

confidence: 99%

TGF-β Family Signaling in Connective Tissue and Skeletal Diseases

MacFarlane

Haupt

Dietz

et al. 2017

Cold Spring Harb Perspect Biol

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“…We have previously reported that augmented BMP-Smad signaling through BMPR1A in cranial neural crest cells results in craniofacial deformity (Komatsu et al, 2013). Because the anterior portion of the craniofacial complex is derived from cranial neural crest cells (Noden and Trainor, 2005;Chai and Maxson, 2006;Mishina and Snider, 2014), we augmented BMP-Smad signaling in the neural crest region by crossing a transgenic mouse line carrying a conditional constitutively active form of Bmpr1a (ca-Bmpr1a) with P0-Cre mice (Yamauchi et al, 1999;Kamiya et al, 2008;Komatsu et al, 2013).…”

Section: Introductionmentioning

confidence: 99%

“…Because the anterior portion of the craniofacial complex is derived from cranial neural crest cells (Noden and Trainor, 2005;Chai and Maxson, 2006;Mishina and Snider, 2014), we augmented BMP-Smad signaling in the neural crest region by crossing a transgenic mouse line carrying a conditional constitutively active form of Bmpr1a (ca-Bmpr1a) with P0-Cre mice (Yamauchi et al, 1999;Kamiya et al, 2008;Komatsu et al, 2013). This genetic manipulation allows an increase in BMP signaling specifically in neural crest-derived tissues, resulting in premature suture fusion of the anterior frontal suture, orbital hypertelorism, short snouts and thinner calvaria.…”

Section: Introductionmentioning

confidence: 99%

Augmented BMP signaling in the neural crest inhibits nasal cartilage morphogenesis by inducing p53-mediated apoptosis

et al. 2015

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Bone morphogenetic protein (BMP) signaling plays many roles in skull morphogenesis. We have previously reported that enhanced BMP signaling through the BMP type IA receptor (BMPR1A) in cranial neural crest cells causes craniosynostosis during postnatal development. Additionally, we observed that 55% of Bmpr1a mutant mice show neonatal lethality characterized by a distended gastrointestinal tract. Here, we show that severely affected mutants exhibit defective nasal cartilage, failure of fusion between the nasal septum and the secondary palate, and higher levels of phosphorylated SMAD1 and SMAD5 in the nasal tissue. TUNEL demonstrated an increase in apoptosis in both condensing mesenchymal tissues and cartilage of the nasal region in mutants. The levels of p53 (TRP53) tumor suppressor protein were also increased in the same tissue. Injection of pifithrin-α, a chemical inhibitor of p53, into pregnant mice prevented neonatal lethality while concomitantly reducing apoptosis in nasal cartilage primordia, suggesting that enhanced BMP signaling induces p53-mediated apoptosis in the nasal cartilage. The expression of Bax and caspase 3, downstream targets of p53, was increased in the mutants; however, the p53 expression level was unchanged. It has been reported that MDM2 interacts with p53 to promote degradation. We found that the amount of MDM2-p53 complex was decreased in all mutants, and the most severely affected mutants had the largest decrease. Our previous finding that the BMP signaling component SMAD1 prevents MDM2-mediated p53 degradation coupled with our new data indicate that augmented BMP signaling induces p53-mediated apoptosis by prevention of p53 degradation in developing nasal cartilage. Thus, an appropriate level of BMP signaling is required for proper craniofacial morphogenesis.

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“…Many genes have also been implicated by studies of mouse genetics (4,(6)(7)(8)(9). These genes are involved in signaling pathways that converge on promotion of osteoblast differentiation and bone formation.…”

mentioning

confidence: 99%

De novo mutations in inhibitors of Wnt, BMP, and Ras/ERK signaling pathways in non-syndromic midline craniosynostosis

Timberlake

Furey

Choi

et al. 2017

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

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Non-syndromic craniosynostosis (NSC) is a frequent congenital malformation in which one or more cranial sutures fuse prematurely. Mutations causing rare syndromic craniosynostoses in humans and engineered mouse models commonly increase signaling of the Wnt, bone morphogenetic protein (BMP), or Ras/ERK pathways, converging on shared nuclear targets that promote bone formation. In contrast, the genetics of NSC is largely unexplored. More than 95% of NSC is sporadic, suggesting a role for de novo mutations. Exome sequencing of 291 parent-offspring trios with midline NSC revealed 15 probands with heterozygous damaging de novo mutations in 12 negative regulators of Wnt, BMP, and Ras/ERK signaling (10.9-fold enrichment, P = 2.4 × 10 −11 ). SMAD6 had 4 de novo and 14 transmitted mutations; no other gene had more than 1. Four familial NSC kindreds had mutations in genes previously implicated in syndromic disease. Collectively, these mutations contribute to 10% of probands. Mutations are predominantly loss-of-function, implicating haploinsufficiency as a frequent mechanism. A common risk variant near BMP2 increased the penetrance of SMAD6 mutations and was overtransmitted to patients with de novo mutations in other genes in these pathways, supporting a frequent two-locus pathogenesis. These findings implicate new genes in NSC and demonstrate related pathophysiology of common non-syndromic and rare syndromic craniosynostoses. These findings have implications for diagnosis, risk of recurrence, and risk of adverse neurodevelopmental outcomes. Finally, the use of pathways identified in rare syndromic disease to find genes accounting for non-syndromic cases may prove broadly relevant to understanding other congenital disorders featuring high locus heterogeneity.

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Augmentation of smad-dependent BMP signaling in neural crest cells causes craniosynostosis in mice

Cited by 89 publications

References 55 publications

TGF-β Family Signaling in Connective Tissue and Skeletal Diseases

TGF-β Family Signaling in Connective Tissue and Skeletal Diseases

Augmented BMP signaling in the neural crest inhibits nasal cartilage morphogenesis by inducing p53-mediated apoptosis

De novo mutations in inhibitors of Wnt, BMP, and Ras/ERK signaling pathways in non-syndromic midline craniosynostosis

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