ClC-7 Deficiency Impairs Tooth Development and Eruption

Wang, He; Pan, Meng Liy; Ni, Jinwen; Zhang, Yutao; Gao, Shan; Jin, Liu; Wang, Zhe; Zhang, Rong; He, Huiming; Wu, Buling; Duan, Xiaohong

doi:10.1038/srep19971

Cited by 14 publications

(15 citation statements)

References 43 publications

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“…In our previous study, we reported two osteopetrosis patients with CLCN7 mutations, who had impacted teeth, enamel dysplasia, malformed teeth, altered tooth eruption and root dysplasia 6-8. A few years later, our group and other groups showed that Clcn7 deficiency displayed dental defects in tooth eruption or root formation 7,9-11. All of these findings provided new insights to further understand the pathological mechanisms of CLCN7 -related osteopetrosis.…”

Section: Introductionsupporting

confidence: 54%

ClC-7 Regulates the Pattern and Early Development of Craniofacial Bone and Tooth

Ji¹,

Li²,

Yang³

et al. 2019

Theranostics

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Human CLCN7 encodes voltage-gated chloride channel 7 (ClC-7); mutations of CLCN7 lead to osteopetrosis which is characterized by increased bone mass and impaired osteoclast function. In our previous clinical practice, we noticed that osteopetrosis patients with CLCN7 mutations had some special deformities in craniofacial morphology and tooth dysplasia. It is unclear whether these phenotypes are the typical features of CLCN7 involved osteopetrosis and whether ClC-7 could regulate the development of craniofacial bone and tooth in some signaling pathways. Methods : First, we collected 80 osteopetrosis cases from the literature and compared their craniofacial and dental phenotypes. Second, four osteopetrosis pedigrees with CLCN7 mutations were recruited from our clinic for gene testing and clinical analysis of their craniofacial and dental phenotypes. Third, we used a zebrafish model with clcn7 morpholino treatment to detect the effects of ClC-7 deficiency on the development of craniofacial and dental phenotypes. General observation, whole mount alcian blue and alizarin red staining, whole mount in situ hybridization, scanning electron microscope observation, lysoSensor staining, Q-PCR and western blotting were performed to observe the in vivo characteristics of craniofacial bone and tooth changes. Fourth, mouse marrow stromal cells were further primarily cultured to detect ClC-7 related mRNA and protein changes using siRNA, Q-PCR and western blotting. Results: Over 84% of osteopetrosis patients in the literature had some typical craniofacial and tooth phenotypes, including macrocephaly, frontal bossing, and changes in shape and proportions of facial skeleton, and these unique features are more severe and frequent in autosomal recessive osteopetrosis than in autosomal dominant osteopetrosis patients. Our four pedigrees with CLCN7 mutations confirmed the aforementioned clinical features. clcn7 knockdown in zebrafish reproduced the craniofacial cartilage defects and various dental malformations combined the decreased levels of col10a1 , sp7 , dlx2b , eve1 , and cx43 . Loss of clcn7 function resulted in lysosomal storage in the brain and jaw as well as downregulated cathepsin K (CTSK). The craniofacial phenotype severity also presented a dose-dependent relationship with the levels of ClC-7 and CTSK. ClC-7/CTSK further altered the balance of TGF-β/BMP signaling pathway, causing elevated TGF-β-like Smad2 signals and reduced BMP-like Smad1/5/8 signals in clcn7 morphants. SB431542 inhibitor of TGF-β pathway partially rescued the aforementioned craniofacial bone and tooth defects of ...

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Section: Introductionsupporting

confidence: 54%

ClC-7 Regulates the Pattern and Early Development of Craniofacial Bone and Tooth

Ji¹,

Li²,

Yang³

et al. 2019

Theranostics

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“…Here, we show that ameloblasts are directly affected by the osteopetrotic V-ATPase a3-R740S mutation. Our results are further supported by a recent study by Wang et al [2016]. In this study, by injecting a3/Tcirg1 Fig.…”

Section: Discussionsupporting

confidence: 92%

V‐ATPases Containing a3 Subunit Play a Direct Role in Enamel Development in Mice

Johnson

Ganß

Wang

et al. 2017

J of Cellular Biochemistry

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Vacuolar H -ATPases (V-ATPases) are ubiquitous multisubunit proton pumps responsible for organellar pH maintenance. Mutations in the a3 subunit of V-ATPases cause autosomal recessive osteopetrosis, a rare disease due to impaired bone resorption. Patients with osteopetrosis also display dental anomalies, such as enamel defects; however, it is not clear whether these enamel abnormalities are a direct consequence of the a3 mutations. We investigated enamel mineralization, spatiotemporal expression of enamel matrix proteins and the a3 protein during tooth development using an osteopetrotic mouse model with a R740S point mutation in the V-ATPase a3 subunit. Histology revealed aberrations in both crown and root development, whereas SEM analysis demonstrated delayed enamel mineralization in homozygous animals. Enamel thickness and mineralization were significantly decreased in homozygous mice as determined by μCT analysis. The expression patterns of the enamel matrix proteins amelogenin, amelotin, and odontogenic ameloblast-associated protein (ODAM) suggested a delay in transition to the maturation stage in homozygous animals. Protein expression of the a3 subunit was detected in ameloblasts in all three genotypes, suggesting that a3-containing V-ATPases play a direct role in amelogenesis, and mutations in a3 delay transition from the secretory to the maturation stage, resulting in hypomineralized and hypoplastic enamel. J. Cell. Biochem. 118: 3328-3340, 2017. © 2017 Wiley Periodicals, Inc.

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“…For the long-term gene silencing experiments, two injections were added every three days till alveolar bones were too hard to perform injection. Mice were harvested for histological analysis at P17 16. Lentivirus to overexpress GATA4 (GATA4 OE) in mouse and blank lentivirus (Ctrl OE) were purchased from GenePharma (Shanghai, China).…”

Section: Methodsmentioning

confidence: 99%

GATA Binding Protein 4 Regulates Tooth Root Dentin Development via FBP1

et al. 2020

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Tooth development is a complex process that is regulated precisely by several signalling pathways and transcription factors. GATA-binding protein 4 (GATA4) is a DNA binding transcription factor, and our previous study showed that GATA4 is a novel regulator of root development. However, it remains unclear whether GATA4 is necessary for odontoblast differentiation and dentin formation. Here, we evaluated the phenotypic changes of Wnt1-Cre;GATA4fl/fl mice. The mutant mice showed defective dentin and short root deformity. The odontoblasts lost polarity instead of exhibiting a shorter height and flattened morphology. Moreover, the expression of several molecules, such as DSPP, COL-1, DCN, and PCNA, were downregulated during mutant tooth development. In vivo, we injected lentivirus to overexpress GATA4 in mice root. The dentin formation and the expression of odonto/osteogenic markers (DSPP, COL-1, DCN) were enhanced in the GATA4 overexpression group. During the in vitro study, the ability of proliferation, migration and odonto/osteogenic differentiation was declined by GATA4 knockdown approach in human dental pulp stem cells (DPSCs). The expression of odonto/osteogenic markers (DSPP, BMP4, RUNX2, OSX, OPN, OCN) was reduced in the shGATA4 group, while overexpressing GATA4 in DPSCs promoted mineralization. Furthermore, an immunoprecipitation-mass spectrometry procedure was used to confirm the interaction between GATA4 and Fructose-1, 6-bisphosphatase 1 (FBP1). We used gain and lose-of-function to delineated the role of GATA4 in regulating FBP1 expression. Knocking down GATA4 in DPSCs resulted in decreased glucose consumption and lactate production. We used small hairpin RNA targeting FBP1 to reduce the expression of FBP1 in DPSCs, which significantly increased glucose consumption and lactate production. Together, the results suggested that GATA4 is important for root formation and odontoblast polarity, as it promotes the growth and differentiation of dental mesenchymal cells around the root and affects the glucose metabolism of DPSCs via the negative regulation of FBP1.

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ClC-7 Deficiency Impairs Tooth Development and Eruption

Cited by 14 publications

References 43 publications

ClC-7 Regulates the Pattern and Early Development of Craniofacial Bone and Tooth

ClC-7 Regulates the Pattern and Early Development of Craniofacial Bone and Tooth

V‐ATPases Containing a3 Subunit Play a Direct Role in Enamel Development in Mice

GATA Binding Protein 4 Regulates Tooth Root Dentin Development via FBP1

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