Noncanonical Transforming Growth Factor β (TGFβ) Signaling in Cranial Neural Crest Cells Causes Tongue Muscle Developmental Defects

Iwata, Junichi; Suzuki, Akiko; Pelikan, Richard; Ho, Thach-Vu; Chai, Yang

doi:10.1074/jbc.m113.493551

Cited by 40 publications

(42 citation statements)

References 48 publications

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“…Similar cases of microglossia occur in other mouse models with mesenchymal mutations, such as Wnt1-Cre; Tgfbr2 fl/fl (Hosokawa et al, 2010;Iwata et al, 2013) and Wnt1-Cre; Alk5 fl/fl (Han et al, 2014) mice. However, in those cases, changes in molecules secreted by the mesenchymal cells directly affect the tongue myogenic progenitors, resulting in altered myogenic proliferation and/or differentiation.…”

Section: Discussionsupporting

confidence: 64%

Disruption of the ERK/MAPK pathway in neural crest cells as a potential cause of Pierre Robin sequence

et al. 2015

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Disrupted ERK1/2 signaling is associated with several developmental syndromes in humans. To understand the function of ERK2 (MAPK1) in the postmigratory neural crest populating the craniofacial region, we studied two mouse models: Wnt1-Cre;Erk2 fl/fl and Osr2-Cre;Erk2 fl/fl . Wnt1-Cre;Erk2 fl/fl mice exhibited cleft palate, malformed tongue, micrognathia and mandibular asymmetry. Cleft palate in these mice was associated with delay/failure of palatal shelf elevation caused by tongue malposition and micrognathia. Osr2-Cre;Erk2 fl/fl mice, in which the Erk2 deletion is restricted to the palatal mesenchyme, did not display cleft palate, suggesting that palatal clefting in Wnt1-Cre; Erk2 fl/fl mice is a secondary defect. Tongues in Wnt1-Cre;Erk2 fl/fl mice exhibited microglossia, malposition, disruption of the muscle patterning and compromised tendon development. The tongue phenotype was extensively rescued after culture in isolation, indicating that it might also be a secondary defect. The primary malformations in Wnt1-Cre;Erk2 fl/fl mice, namely micrognathia and mandibular asymmetry, are linked to an early osteogenic differentiation defect. Collectively, our study demonstrates that mutation of Erk2 in neural crest derivatives phenocopies the human Pierre Robin sequence and highlights the interconnection of palate, tongue and mandible development. Because the ERK pathway serves as a crucial point of convergence for multiple signaling pathways, our study will facilitate a better understanding of the molecular regulatory mechanisms of craniofacial development.

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Section: Discussionsupporting

confidence: 64%

Disruption of the ERK/MAPK pathway in neural crest cells as a potential cause of Pierre Robin sequence

et al. 2015

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“…CNC-specific Tgfbr2 mutant (Tgfbr2 fl/fl ;Wnt1-Cre) mice exhibit muscle abnormalities in the tongue (Iwata et al, 2013b) and soft palate (supplementary material Fig. S6), following defects in cell proliferation and maturation or organization.…”

Section: Research Articlementioning

confidence: 99%

“…Immunoblotting was performed as described previously (Iwata et al, 2012;Iwata et al, 2013b). Antibodies used for immunoblotting were as follows: mouse monoclonal antibodies against DKK1 (Santa Cruz Biotechnology), active form of β-catenin (ABC) and GAPDH (Millipore), and rabbit polyclonal antibody against phosphorylated β-catenin (Cell Signaling Technology).…”

Section: Immunoblotting Analysismentioning

confidence: 99%

TGFβ regulates epithelial-mesenchymal interactions through WNT signaling activity to control muscle development in the soft palate

et al. 2014

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Clefting of the soft palate occurs as a congenital defect in humans and adversely affects the physiological function of the palate. However, the molecular and cellular mechanism of clefting of the soft palate remains unclear because few animal models exhibit an isolated cleft in the soft palate. Using three-dimensional microCT images and histological reconstruction, we found that loss of TGFβ signaling in the palatal epithelium led to soft palate muscle defects in Tgfbr2 fl/fl ;K14-Cre mice. Specifically, muscle mass was decreased in the soft palates of Tgfbr2 mutant mice, following defects in cell proliferation and differentiation. Gene expression of Dickkopf (Dkk1 and Dkk4), negative regulators of WNT-β-catenin signaling, is upregulated in the soft palate of

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“…Tongue primordium is comprised of mesenchyme cells derived from cranial neural crest cells (CNCCs), ectoderm-derived lingual epithelium in the distal portion and the endoderm-derived proximal portion (2). The myoblasts migrated from the occipital somites surround the CNCCs during the process of tongue development (2).…”

Section: Introductionmentioning

confidence: 99%

“…However, the tongue muscle also exhibits unique characteristics that are distinct from those of other skeletal muscles, and different regulatory mechanisms may be in place. Previous studies demonstrated that transforming growth factor β1, Smad4 and fibroblast growth factor 6 signaling pathways regulate myogenic differentiation and myoblast fusion during tongue development (2,3). It should be noted that most previous studies focused on embryonic development of mice tongues, whereas the postnatal development of the tongue has remained to be fully explored.…”

Section: Introductionmentioning

confidence: 99%

Histological study of postnatal development of mouse tongues

Jiang¹,

Chen

2017

Exp Ther Med

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Abstract. Numerous factors, including trauma, tumors and myophagism, may lead to tongue defects, which are mostly repaired via muscular flaps. However, these methods cannot restore the muscular function and gustation function of the tongue. Intensive research on tongue development may offer useful clues for tongue regeneration based on tissue engineering or stem cell therapy. In the present study, staining results revealed that tongue muscle fibers became larger, mature and stronger, and the foliate and fungiform papillae also became mature from newborn to adult C57BL/6J genetic background mice. Immunofluorescence staining and polymerase chain reaction results revealed that C-kit was dynamically expressed in muscle cells, as well as in foliate and fungiform papilla cells from newborn to adult stages. The expression level decreased from P1 to P15 and increased at P90. The immunofluorescence staining results revealed that Ki-67 was expressed in muscle cells and papilla cells from newborn to adult stages, and high expression was observed at P6 and P15. In addition, the immunofluorescence staining results also demonstrated that msh homeobox 2 (Msx2) was dynamically expressed in postnatal tongue muscle cells; however, almost no expression was detected in papilla cells. There was relative high expression level of Msx2 at P1 and P6 stages, but this gradually decreased from P15, and it was expressed primarily in the muscle cells located in the marginal zone of the tongue at P90. These findings suggest that the amount of c-kit-expressing precursor cells in tongue muscle and papilla cells increases to promote tongue development at the early postnatal stage and to maintain homeostasis and functional adaptation of the tongue in the adult stage. Furthermore, Msx2 may serve an important role in postnatal tongue muscle development. The present study also suggests that C-kit and Msx2 may be used as cell markers for postnatal tongue regeneration and self-repair, and may provide an approach for developing treatment methods for tongue diseases with a postnatal onset. IntroductionNormal tongue development has a crucial role in craniofacial development, particularly for jaw and palate development (1). Tongue primordium is comprised of mesenchyme cells derived from cranial neural crest cells (CNCCs), ectoderm-derived lingual epithelium in the distal portion and the endoderm-derived proximal portion (2). The myoblasts migrated from the occipital somites surround the CNCCs during the process of tongue development (2). Core myogenic regulators, such as MyoD, myogenic factor (Myf)5 and Myf6 (also known as MRF4) have important roles in tongue muscle development (3). However, the tongue muscle also exhibits unique characteristics that are distinct from those of other skeletal muscles, and different regulatory mechanisms may be in place. Previous studies demonstrated that transforming growth factor β1, Smad4 and fibroblast growth factor 6 signaling pathways regulate myogenic differentiation and myoblast fusion during tongue development (2,3...

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Noncanonical Transforming Growth Factor β (TGFβ) Signaling in Cranial Neural Crest Cells Causes Tongue Muscle Developmental Defects

Cited by 40 publications

References 48 publications

Disruption of the ERK/MAPK pathway in neural crest cells as a potential cause of Pierre Robin sequence

Disruption of the ERK/MAPK pathway in neural crest cells as a potential cause of Pierre Robin sequence

TGFβ regulates epithelial-mesenchymal interactions through WNT signaling activity to control muscle development in the soft palate

Histological study of postnatal development of mouse tongues

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