Augmented BMPRIA-Mediated BMP Signaling in Cranial Neural Crest Lineage Leads to Cleft Palate Formation and Delayed Tooth Differentiation

Li, Lü; Wang, Ying; Lin, Minkui; Yuan, Guohua; Yang, Guobin; Zheng, Yanhui

doi:10.1371/journal.pone.0066107

Cited by 37 publications

(48 citation statements)

References 51 publications

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“…We have shown previously that elevated BMP signaling, either by inactivating Noggin or by forced expression of a constitutively active form of BMPRIa ( BmprIa ) in CNC lineage or in epithelium, disrupts normal development of the palate and tooth (He et al, 2010; Li et al, 2013). To further investigate the potential role of BMP signaling in craniofacial morphogenesis, we generated pMes-Bmp4 conditional transgenic mice.…”

Section: Resultsmentioning

confidence: 99%

“…Among these type I receptors, BmprIa has been shown to play an essential role in craniofacial development (Li et al, 2011; Li et al, 2013; Liu et al, 2005). Since Wnt1Cre -driven expression of a constitutively active form of BMPR-IB ( caBmprIb ) did not produce any visible phenotype in mice (Li et al, 2011), we reevaluated craniofacial phenotype of mice expressing caBmprIa in CNC lineage ( Wnt1Cre;pMes-caBmprIa ) mice and confirmed a lack of syngnathia-like phenotype in these mice (data not shown). Histological analysis also confirmed the origin of palatal shelves, although dramatically deformed, from the maxillary region in Wnt1Cre;pMes-caBmprIa mice (Fig.…”

Section: Resultsmentioning

confidence: 99%

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Directed Bmp4 expression in neural crest cells generates a genetic model for the rare human bony syngnathia birth defect

Xiong

et al. 2014

Developmental Biology

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Congenital bony syngnathia, a rare but severe human birth defect, is characterized by bony fusion of the mandible to the maxilla. However, the genetic mechanisms underlying this birth defect are poorly understood, largely due to limitation of available animal models. Here we present evidence that transgenic expression of Bmp4 in neural crest cells causes a series of craniofacial malformations in mice, including a bony fusion between the maxilla and hypoplastic mandible, resembling the bony syngnathia syndrome in humans. In addition, the anterior portion of the palatal shelves emerged from the mandibular arch instead of the maxilla in the mutants. Gene expression assays showed an altered expression of several facial patterning genes, including Hand2, Dlx2, Msx1, Barx1, Foxc2 and Fgf8, in the maxillary and mandibular processes of the mutants, indicating mis-patterned cranial neural crest (CNC) derived cells in the facial region. However, despite of formation of cleft palate and ectopic cartilage, forced expression of a constitutively active form of BMP receptor-Ia (caBmprIa) in CNC lineage did not produce the syngnathia phenotype, suggesting a non-cell autonomous effect of the augmented BMP4 signaling. Our studies demonstrate that aberrant BMP4-mediated signaling in CNC cells leads to mis-patterned facial skeleton and congenital bony syngnathia, and suggest an implication of mutations in BMP signaling pathway in human bony syngnathia.

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Section: Resultsmentioning

confidence: 99%

Section: Resultsmentioning

confidence: 99%

Directed Bmp4 expression in neural crest cells generates a genetic model for the rare human bony syngnathia birth defect

Xiong

et al. 2014

Developmental Biology

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“…Mouse genetic manipulation studies have revealed a requirement for precise regulation of BMP signaling in craniofacial development (Bonilla-Claudio et al, 2012; Li et al, 2013; Wang et al, 2013). …”

Section: Introductionmentioning

confidence: 99%

Multiple tissue-specific requirements for the BMP antagonist Noggin in development of the mammalian craniofacial skeleton

Matsui

Klingensmith

2014

Developmental Biology

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Proper morphogenesis is essential for both form and function of the mammalian craniofacial skeleton, which consists of more than twenty small cartilages and bones. Skeletal elements that support the oral cavity are derived from cranial neural crest cells (NCCs) that develop in the maxillary and mandibular buds of pharyngeal arch 1 (PA1). Bone Morphogenetic Protein (BMP) signaling has been implicated in most aspects of craniofacial skeletogenesis, including PA1 development. However, the roles of the BMP antagonist Noggin in formation of the craniofacial skeleton remain unclear, in part because of its multiple domains of expression during formative stages. Here we used a tissue-specific gene ablation approach to assess roles of Noggin (Nog) in two different tissue domains potentially relevant to mandibular and maxillary development. We found that the axial midline domain of Nog expression is critical to promote PA1 development in early stages, necessary for adequate outgrowth of the mandibular bud. Subsequently, Nog expression in NCCs regulates craniofacial cartilage and bone formation. Mice lacking Nog in NCCs have an enlarged mandible that results from increased cell proliferation in and around Meckel’s cartilage. These mutants also show complete secondary cleft palate, most likely due to inhibition of posterior palatal shelf elevation by disrupted morphology of the developing skull base. Our findings demonstrate multiple roles of Noggin in different domains for craniofacial skeletogenesis, and suggest an indirect mechanism for secondary cleft palate in Nog mutants that may be relevant to human cleft palate as well.

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“…We have shown previously that the expression of caBmprIa in CNC lineage induces ectopic activation of Smad1/5/8 signaling as well as p38 signaling in the developing palatal shelves [51]. We therefore set to examine alterations in BMP canonical and non-canonical signaling pathways in the condylar cartilage of Wnt1-Cre;pMes-caBmprIa mice by immunohistochemistry.…”

Section: Resultsmentioning

confidence: 99%

BMPRIA Mediated Signaling Is Essential for Temporomandibular Joint Development in Mice

Liu

et al. 2014

PLoS ONE

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The central importance of BMP signaling in the development and homeostasis of synovial joint of appendicular skeleton has been well documented, but its role in the development of temporomandibular joint (TMJ), also classified as a synovial joint, remains completely unknown. In this study, we investigated the function of BMPRIA mediated signaling in TMJ development in mice by transgenic loss-of- and gain-of-function approaches. We found that BMPRIA is expressed in the cranial neural crest (CNC)-derived developing condyle and glenoid fossa, major components of TMJ, as well as the interzone mesenchymal cells. Wnt1-Cre mediated tissue specific inactivation of BmprIa in CNC lineage led to defective TMJ development, including failure of articular disc separation from a hypoplastic condyle, persistence of interzone cells, and failed formation of a functional fibrocartilage layer on the articular surface of the glenoid fossa and condyle, which could be at least partially attributed to the down-regulation of Ihh in the developing condyle and inhibition of apoptosis in the interzone. On the other hand, augmented BMPRIA signaling by Wnt1-Cre driven expression of a constitutively active form of BmprIa (caBmprIa) inhibited osteogenesis of the glenoid fossa and converted the condylar primordium from secondary cartilage to primary cartilage associated with ectopic activation of Smad-dependent pathway but inhibition of JNK pathway, leading to TMJ agenesis. Our results present unambiguous evidence for an essential role of finely tuned BMPRIA mediated signaling in TMJ development.

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Augmented BMPRIA-Mediated BMP Signaling in Cranial Neural Crest Lineage Leads to Cleft Palate Formation and Delayed Tooth Differentiation

Cited by 37 publications

References 51 publications

Directed Bmp4 expression in neural crest cells generates a genetic model for the rare human bony syngnathia birth defect

Directed Bmp4 expression in neural crest cells generates a genetic model for the rare human bony syngnathia birth defect

Multiple tissue-specific requirements for the BMP antagonist Noggin in development of the mammalian craniofacial skeleton

BMPRIA Mediated Signaling Is Essential for Temporomandibular Joint Development in Mice

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