Transforming Growth Factor-Beta and Sonic Hedgehog Signaling in Palatal Epithelium Regulate Tenascin-C Expression in Palatal Mesenchyme During Soft Palate Development

Ohki, Shirabe; Oka, Kyoko; Ogata, Kayoko; Okuhara, Shigeru; Rikitake, Mihoko; Toda-Nakamura, Masako; Tamura, Shougo; Ozaki, Masao; Iseki, Sachiko; Sakai, Takayoshi

doi:10.3389/fphys.2020.00532

Cited by 13 publications

(10 citation statements)

References 48 publications

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“…This is consistent with previous studies which have shown that ethanol can affect TGFβ signalling in the brain [65–68] and the articular cartilage [69]. Defects in cleft palate formation are evident in FASD models and this process requires crosstalk between the TGFβ pathway and Sonic hedgehog (Shh) [70, 71]. Interestingly, the detrimental effects of PAE can be partially remedied by increased Shh [31], adding further evidence that these may be key pathways in the underlying pathology of FASD.…”

Section: Discussionsupporting

confidence: 92%

Sexually dimorphic effects of prenatal alcohol exposure on the murine skeleton

Bourne,

Jayash,

Michels

et al. 2024

Preprint

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Background: Prenatal alcohol exposure (PAE) can result in lifelong disabilities known as foetal alcohol spectrum disorder (FASD) and is associated with childhood growth deficiencies and increased bone fracture risk. However, the effects of PAE on the adult skeleton remain unclear and any potential sexual dimorphism is undetermined. Therefore, we utilised a murine model to examine sex differences with PAE on in vitro bone formation, and in the juvenile and adult skeleton. Methods: Pregnant C57BL/6J female mice received 5% ethanol in their drinking water during gestation. Primary calvarial osteoblasts were isolated from neonatal offspring and mineralised bone nodule formation and gene expression assessed. Skeletal phenotyping of 4- and 12-week-old male and female offspring was conducted by micro-computed tomography (uCT), 3-point bending, growth plate analyses, and histology. Results: Osteoblasts from male and female PAE mice displayed reduced bone formation, compared to control (less than or equal to 30%). Bglap and Ahsg were upregulated with PAE in both sexes compared to control, whereas Vegfa, Bmp6, Tgfbr1 and Flt1 were downregulated in PAE male osteoblasts only. In 12-week-old mice, uCT analysis revealed a sex and exposure interaction across several trabecular bone parameters. PAE was detrimental to the trabecular compartment in male mice compared to control, yet PAE females were unaffected. Both male and female mice had significant reductions in cortical parameters with PAE. Whilst male mice were negatively affected along the tibia length, females were only distally affected. Posterior cortical porosity was increased in PAE females only. Mechanical testing revealed PAE males had significantly reduced bone stiffness compared to controls; maximum load and yield was reduced in both sexes. PAE had no effect on total body weight or tibial bone length in either sex. However, total growth plate width in male PAE mice compared to control was reduced, whilst female PAE mice were unaffected. 4-week-old mice did not display the altered skeletal phenotype with PAE observed in 12-week-old animals. Conclusions: Evidence herein suggests for the first time that PAE exerts divergent sex effects on the skeleton, possibly influenced by underlying sex specific transcriptional mechanisms of osteoblasts. Establishing these sex differences will support future policies and clinical management of FASD.

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Section: Discussionsupporting

confidence: 92%

Sexually dimorphic effects of prenatal alcohol exposure on the murine skeleton

Bourne,

Jayash,

Michels

et al. 2024

Preprint

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“…Intriguingly, Noggin was reported to induce Scx transcription during the early specification of limb tendons (Schweitzer et al, 2001), while in this study, the overexpressed Noggin inhibited the tenogenesis. The contradictory phenomena may result from the signaling other than BMP-Smad signaling, which was altered by the overexpressed Noggin (Ohki et al, 2020). Actually, the decreased Scx transcription in both the Osr2-cre KI ;pMes-Noggin and Myf5cre;pMes-Noggin soft palates was supposed to be regarded as a sign of the impaired tenogenic differentiation and maturation, because Scx was also essential for the maintenance of tendons.…”

Section: Discussionmentioning

confidence: 99%

Noggin Overexpression Impairs the Development of Muscles, Tendons, and Aponeurosis in Soft Palates by Disrupting BMP-Smad and Shh-Gli1 Signaling

Deng

Wang

et al. 2021

Front. Cell Dev. Biol.

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The roles of bone morphogenetic protein (BMP) signaling in palatogenesis were well documented in the developing hard palate; however, little is known about how BMP signaling regulates the development of soft palate. In this study, we overexpressed Noggin transgene via Osr2-creKI allele to suppress BMP signaling in the developing soft palate. We found that BMP-Smad signaling was detected in the palatal muscles and surrounding mesenchyme. When BMP-Smad signaling was suppressed by the overexpressed Noggin, the soft palatal shelves were reduced in size with the hypoplastic muscles and the extroversive hypophosphatasia (HPP). The downregulated cell proliferation and survival in the Osr2-creKI;pMes-Noggin soft palates were suggested to result from the repressed Shh transcription and Gli1 activity, implicating that the BMP-Shh-Gli1 network played a similar role in soft palate development as in the hard palate. The downregulated Sox9, Tenascin-C (TnC), and Col1 expression in Osr2-creKI;pMes-Noggin soft palate indicated the impaired differentiation of the aponeurosis and tendons, which was suggested to result in the hypoplasia of palatal muscles. Intriguingly, in the Myf5-creKI;pMes-Noggin and the Myf5-creKI;Rosa26R-DTA soft palates, the hypoplastic or abrogated muscles affected little the fusion of soft palate. Although the Scx, Tnc, and Co1 transcription was significantly repressed in the tenogenic mesenchyme of the Myf5-creKI;pMes-Noggin soft palate, the Sox9 expression, and the Tnc and Col1 transcription in aponeurosis mesenchyme were almost unaffected. It implicated that the fusion of soft palate was controlled by the mesenchymal clues at the tensor veli palatini (TVP) and levator veli palatini (LVP) levels, but by the myogenic components at the palatopharyngeus (PLP) level.

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“…Sonic hedgehog signaling is essential for orofacial development and mediates epithelialmesenchymal interactions that control palatal outgrowth [10]. A recent study revealed that TGFβ and SHH together regulate the expression of tenascin-C in developing soft palates [140]. Tenascin-C is a glycoprotein of the extracellular matrix, and its expression overlays the migratory routes of cranial neural crest cells while forming future palate [141].…”

Section: Sonic Hedgehog Signalingmentioning

confidence: 99%

Orofacial Cleft and Mandibular Prognathism—Human Genetics and Animal Models

Jaruga

Ksiazkiewicz

Kuźniarz

et al. 2022

IJMS

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Many complex molecular interactions are involved in the process of craniofacial development. Consequently, the network is sensitive to genetic mutations that may result in congenital malformations of varying severity. The most common birth anomalies within the head and neck are orofacial clefts (OFCs) and prognathism. Orofacial clefts are disorders with a range of phenotypes such as the cleft of the lip with or without cleft palate and isolated form of cleft palate with unilateral and bilateral variations. They may occur as an isolated abnormality (nonsyndromic—NSCLP) or coexist with syndromic disorders. Another cause of malformations, prognathism or skeletal class III malocclusion, is characterized by the disproportionate overgrowth of the mandible with or without the hypoplasia of maxilla. Both syndromes may be caused by the presence of environmental factors, but the majority of them are hereditary. Several mutations are linked to those phenotypes. In this review, we summarize the current knowledge regarding the genetics of those phenotypes and describe genotype–phenotype correlations. We then present the animal models used to study these defects.

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Transforming Growth Factor-Beta and Sonic Hedgehog Signaling in Palatal Epithelium Regulate Tenascin-C Expression in Palatal Mesenchyme During Soft Palate Development

Cited by 13 publications

References 48 publications

Sexually dimorphic effects of prenatal alcohol exposure on the murine skeleton

Sexually dimorphic effects of prenatal alcohol exposure on the murine skeleton

Noggin Overexpression Impairs the Development of Muscles, Tendons, and Aponeurosis in Soft Palates by Disrupting BMP-Smad and Shh-Gli1 Signaling

Orofacial Cleft and Mandibular Prognathism—Human Genetics and Animal Models

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