Constitutively active mutation of ACVR1 in oral epithelium causes submucous cleft palate in mice

Noda, Kazuo; Mishina, Yuji; Komatsu, Yoshihiro

doi:10.1016/j.ydbio.2015.06.014

Cited by 20 publications

(22 citation statements)

References 40 publications

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“…Staining of bone and cartilage of embryos with Alizarin red/ Alcian blue was carried out as described previously (60). H&E staining, immunofluorescent staining, and TUNEL assays of paraffin sections were performed as described previously (61). The von Kossa staining was performed using a von Kossa staining kit (Abcam; ab150687).…”

Section: Methodsmentioning

confidence: 99%

Canonical and noncanonical intraflagellar transport regulates craniofacial skeletal development

Noda¹,

Kitami²,

Kitami

et al. 2016

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

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The primary cilium is a cellular organelle that coordinates signaling pathways critical for cell proliferation, differentiation, survival, and homeostasis. Intraflagellar transport (IFT) plays a pivotal role in assembling primary cilia. Disruption and/or dysfunction of IFT components can cause multiple diseases, including skeletal dysplasia. However, the mechanism by which IFT regulates skeletogenesis remains elusive. Here, we show that a neural crest-specific deletion of intraflagellar transport 20 (Ift20) in mice compromises ciliogenesis and intracellular transport of collagen, which leads to osteopenia in the facial region. Whereas platelet-derived growth factor receptor alpha (PDGFRα) was present on the surface of primary cilia in wildtype osteoblasts, disruption of Ift20 down-regulated PDGFRα production, which caused suppression of PDGF-Akt signaling, resulting in decreased osteogenic proliferation and increased cell death. Although osteogenic differentiation in cranial neural crest (CNC)-derived cells occurred normally in Ift20-mutant cells, the process of mineralization was severely attenuated due to delayed secretion of type I collagen. In control osteoblasts, procollagen was easily transported from the endoplasmic reticulum (ER) to the Golgi apparatus. By contrast, despite having similar levels of collagen type 1 alpha 1 (Col1a1) expression, Ift20 mutants did not secrete procollagen because of dysfunctional ER-to-Golgi trafficking. These data suggest that in the multipotent stem cells of CNCs, IFT20 is indispensable for regulating not only ciliogenesis but also collagen intracellular trafficking. Our study introduces a unique perspective on the canonical and noncanonical functions of IFT20 in craniofacial skeletal development.cranial neural crest cells | intracellular trafficking | intraflagellar transport | PDGF signaling | primary cilia

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Section: Methodsmentioning

confidence: 99%

Canonical and noncanonical intraflagellar transport regulates craniofacial skeletal development

Noda¹,

Kitami²,

Kitami

et al. 2016

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

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“…The type I receptor ActRI/ALK-2 has also been proposed to mediate TGF-b3 signals in the palate epithelium, possibly acting in a less potent manner (Fig. 3) (Noda et al 2015). However, ActRI acts during palatal fusion as a BMP signaling receptor, which activates BMP-specific Smad proteins (Noda et al 2015).…”

Section: Cell Cycle Arrest Migration Apoptosismentioning

confidence: 99%

“…3) (Noda et al 2015). However, ActRI acts during palatal fusion as a BMP signaling receptor, which activates BMP-specific Smad proteins (Noda et al 2015). An activated mutant of ActRI induces BMP Smad signaling and causes cleft palate because the epithelial layer in the medial edge fails to undergo apoptosis and has increased proliferation, and the mesenchymal and muscle layers fail to fuse (Noda et al 2015).…”

Section: Cell Cycle Arrest Migration Apoptosismentioning

confidence: 99%

“…However, ActRI acts during palatal fusion as a BMP signaling receptor, which activates BMP-specific Smad proteins (Noda et al 2015). An activated mutant of ActRI induces BMP Smad signaling and causes cleft palate because the epithelial layer in the medial edge fails to undergo apoptosis and has increased proliferation, and the mesenchymal and muscle layers fail to fuse (Noda et al 2015). In a related but seemingly opposite scenario, mice with a gain-of-function mutation in the BMPRIA receptor show a variety of defects, mostly associated with craniofacial development, because of malformations in the neural crest (Hayano et al 2015).…”

Section: Cell Cycle Arrest Migration Apoptosismentioning

confidence: 99%

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TGF-β Family Signaling in Epithelial Differentiation and Epithelial–Mesenchymal Transition

Kahata

Dadras

Moustakas

2017

Cold Spring Harb Perspect Biol

100

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Epithelia exist in the animal body since the onset of embryonic development; they generate tissue barriers and specify organs and glands. Through epithelial-mesenchymal transitions (EMTs), epithelia generate mesenchymal cells that form new tissues and promote healing or disease manifestation when epithelial homeostasis is challenged physiologically or pathologically. Transforming growth factor-βs (TGF-βs), activins, bone morphogenetic proteins (BMPs), and growth and differentiation factors (GDFs) have been implicated in the regulation of epithelial differentiation. These TGF-β family ligands are expressed and secreted at sites where the epithelium interacts with the mesenchyme and provide paracrine queues from the mesenchyme to the neighboring epithelium, helping the specification of differentiated epithelial cell types within an organ. TGF-β ligands signal via Smads and cooperating kinase pathways and control the expression or activities of key transcription factors that promote either epithelial differentiation or mesenchymal transitions. In this review, we discuss evidence that illustrates how TGF-β family ligands contribute to epithelial differentiation and induce mesenchymal transitions, by focusing on the embryonic ectoderm and tissues that form the external mammalian body lining.

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“…BMP signaling is also involved in regulating maturation and ossification of the fused palate. A constitutively active mutation of Acvr1 in oral epithelium causes a submucosal cleft palate in mice [105]. Enhanced BMP signaling resulted in altered proliferation and apoptosis in the medial edge epithelium leading to its persistence, thereby preventing fusion of palatal mesenchyme and muscle tissue (Fig.…”

Section: Bmp Signaling During Palate Morphogenesismentioning

confidence: 99%

Common mechanisms in development and disease: BMP signaling in craniofacial development

Graf

Malik

Hayano

et al. 2016

Cytokine & Growth Factor Reviews

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BMP signaling is one of the key pathways regulating craniofacial development. It is involved in the early pattering of the head, the development of cranial neural crest cells, and facial patterning. It regulates development of its mineralized structures, such as cranial bones, maxilla, mandible, palate, and teeth. Targeted mutations in the mouse have been instrumental to delineate the functional involvement of this signaling network in different aspects of craniofacial development. Gene polymorphisms and mutations in BMP pathway genes have been associated with various non-syndromic and syndromic human craniofacial malformations. The identification of intricate cellular interactions and underlying molecular pathways illustrate the importance of local fine-regulation of Bmp signaling to control proliferation, apoptosis, epithelial-mesenchymal interactions, and stem/progenitor differentiation during craniofacial development. Thus, BMP signaling contributes both to shape and functionality of our facial features. BMP signaling also regulates postnatal craniofacial growth and is associated with dental structures life-long. A more detailed understanding of BMP function in growth, homeostasis, and repair of postnatal craniofacial tissues will contribute to our ability to rationally manipulate this signaling network in the context of tissue engineering.

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Constitutively active mutation of ACVR1 in oral epithelium causes submucous cleft palate in mice

Cited by 20 publications

References 40 publications

Canonical and noncanonical intraflagellar transport regulates craniofacial skeletal development

Canonical and noncanonical intraflagellar transport regulates craniofacial skeletal development

TGF-β Family Signaling in Epithelial Differentiation and Epithelial–Mesenchymal Transition

Common mechanisms in development and disease: BMP signaling in craniofacial development

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