SHP2-Deficiency in Chondrocytes Deforms Orofacial Cartilage and Ciliogenesis in Mice

Kamiya, Nobuhiro; Shen, Jingling; Noda, Kazuo; Kitami, Megumi; Feng, Gen Sheng; Chen, Di; Komatsu, Yoshihiro

doi:10.1002/jbmr.2541

Cited by 13 publications

(12 citation statements)

References 20 publications

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“…Consistent with the previous findings, conditional deletion of Ptpn11 gene that codes for Shp2, a tyrosine phosphatase required for the activation of the Ras/Erk cascade, results in severe malformation of the mandibular condyle in Col2a1-Cre;Shp2 LoxP/LoxP mice (Ref. 23). Taken together, both activating and suppressive alterations in the ERK pathway seem to lead to similar phenotypes in the affected individuals implying that possibly orofacial development is sensitive to the exact location, the timing or even the activation level of this particular signalling cascade.…”

Section: Ras/erk Pathway In Orofacial Malformationssupporting

confidence: 88%

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Craniofacial, orofacial and dental disorders: the role of the RAS/ERK pathway

Vogiatzi

Mavrothalassitis

2019

Expert Rev. Mol. Med.

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Deviations from the precisely coordinated programme of human head development can lead to craniofacial and orofacial malformations often including a variety of dental abnormalities too. Although the aetiology is still unknown in many cases, during the last decades different intracellular signalling pathways have been genetically linked to specific disorders. Among these pathways, the RAS/extracellular signal-regulated kinase (ERK) signalling cascade is the focus of this review since it encompasses a large group of genes that when mutated cause some of the most common and severe developmental anomalies in humans. We present the components of the RAS/ERK pathway implicated in craniofacial and orodental disorders through a series of human and animal studies. We attempt to unravel the specific molecular targets downstream of ERK that act on particular cell types and regulate key steps in the associated developmental processes. Finally we point to ambiguities in our current knowledge that need to be clarified before RAS/ERK-targeting therapeutic approaches can be implemented.

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Section: Ras/erk Pathway In Orofacial Malformationssupporting

confidence: 88%

“…In mandibular condyles, Shp2 via Erk1/2 phosphorylation is proposed to induce the expression of the intraflagellar transport complexes (Ref. 23). These complexes are necessary for the formation of the primary cilia and the differentiation of chondrocytes.…”

Section: Ras/erk Pathway In Orofacial Malformationsmentioning

confidence: 99%

Craniofacial, orofacial and dental disorders: the role of the RAS/ERK pathway

Vogiatzi

Mavrothalassitis

2019

Expert Rev. Mol. Med.

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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).…”

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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“…Kamiya et al reported that SHP2 deficiency in orofacial cartilage chondrocytes causes severe mandibular condyle deformity due to expanded cartilage in the trabecular area, along with a reduction in the number and length of cilia. 224 Mechanistically, SHP2 may regulate ciliogenesis and cilia-mediated mechanotransduction in chondrocytes by positively influencing intraflagellar transport components (Fig. 8 ).…”

Section: Ptps In Chondrocyte Development and Cartilage Homeostasismentioning

confidence: 99%

Protein tyrosine phosphatases in skeletal development and diseases

et al. 2022

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Skeletal development and homeostasis in mammals are modulated by finely coordinated processes of migration, proliferation, differentiation, and death of skeletogenic cells originating from the mesoderm and neural crest. Numerous molecular mechanisms are involved in these regulatory processes, one of which is protein posttranslational modifications, particularly protein tyrosine phosphorylation (PYP). PYP occurs mainly through the action of protein tyrosine kinases (PTKs), modifying protein enzymatic activity, changing its cellular localization, and aiding in the assembly or disassembly of protein signaling complexes. Under physiological conditions, PYP is balanced by the coordinated action of PTKs and protein tyrosine phosphatases (PTPs). Dysregulation of PYP can cause genetic, metabolic, developmental, and oncogenic skeletal diseases. Although PYP is a reversible biochemical process, in contrast to PTKs, little is known about how this equilibrium is modulated by PTPs in the skeletal system. Whole-genome sequencing has revealed a large and diverse superfamily of PTP genes (over 100 members) in humans, which can be further divided into cysteine (Cys)-, aspartic acid (Asp)-, and histidine (His)-based PTPs. Here, we review current knowledge about the functions and regulatory mechanisms of 28 PTPs involved in skeletal development and diseases; 27 of them belong to class I and II Cys-based PTPs, and the other is an Asp-based PTP. Recent progress in analyzing animal models that harbor various mutations in these PTPs and future research directions are also discussed. Our literature review indicates that PTPs are as crucial as PTKs in supporting skeletal development and homeostasis.

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SHP2-Deficiency in Chondrocytes Deforms Orofacial Cartilage and Ciliogenesis in Mice

Cited by 13 publications

References 20 publications

Craniofacial, orofacial and dental disorders: the role of the RAS/ERK pathway

Craniofacial, orofacial and dental disorders: the role of the RAS/ERK pathway

Canonical and noncanonical intraflagellar transport regulates craniofacial skeletal development

Protein tyrosine phosphatases in skeletal development and diseases

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