Msx1 Mutations

Wang, Y.; Kong, Han-Bae; Mues, Gabriele; D’Souza, Rena N.

doi:10.1177/0022034510387430

Cited by 32 publications

(17 citation statements)

References 27 publications

(40 reference statements)

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“…The mutation cosegregated with the oligodontia phenotype in this family with complete penetrance. Previous studies have identified more than ten mutations related to nonsyndromic tooth agenesis in MSX1 [ 10 – 16 , 23 – 26 ]. MSX1-deficient mice showed a series of abnormalities in skeletal and tooth development, including the absence of incisor tooth buds and developmental retardation of molar tooth buds [ 9 ].…”

Section: Discussionmentioning

confidence: 99%

A novel mutation of MSX1 in oligodontia inhibits odontogenesis of dental pulp stem cells via the ERK pathway

Xin

Zhang

et al. 2018

Stem Cell Res Ther

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BackgroundTooth agenesis, one of the most common developmental anomalies, can affect the function and esthetics of patients. The aim of the present study was to identify genetic clues for familial tooth agenesis and explore the underlying mechanisms, focusing on the role of human dental pulp stem cells (hDPSCs).MethodsWe applied Sanger sequencing to identify the cause of oligodontia in a Chinese family. DNA transfection and functional analysis in DPSCs was also performed to explore the impact of the identified mutation on this phenotype.ResultsIn this study, a novel frameshift mutation, the twenty-nucleotide deletion (c.128_147del20, p.Met43Serfsx125), in exon1 of MSX1 was detected in a Chinese family causing autosomal dominant nonsyndromic oligodontia. The mutation cosegregated with the tooth agenesis phenotype in this family. DPSCs transfected with mutant MSX1 plasmid showed decreased capacity of osteo/odontogenic differentiation with a lower expression level of dentin sialophosphoprotein (DSPP) and bone sialoprotein (BSP) compared with those transfected with control MSX1 plasmid. Mechanically, control MSX1 showed nuclear localization while the mutant MSX1 inhibited its nuclear translocation and localized on the cytoplasm to inhibit ERK phosphorylation. Furthermore, we inhibited the ERK pathway using ERK inhibitor (U0126) treatment in control MSX1-transfected DPSCs which could downregulate mineralized nodule formation and the expression of odontogenic genes.ConclusionWe demonstrated a novel MSX1 mutation causing familial nonsyndromic oligodontia and mechanically MSX1 regulates odontogenesis through the ERK signaling pathway in human dental pulp stem cells.Electronic supplementary materialThe online version of this article (10.1186/s13287-018-0965-3) contains supplementary material, which is available to authorized users.

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Section: Discussionmentioning

confidence: 99%

A novel mutation of MSX1 in oligodontia inhibits odontogenesis of dental pulp stem cells via the ERK pathway

Xin

Zhang

et al. 2018

Stem Cell Res Ther

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“…However, the best characterized positive feedback loop involving MSX2 and a secreted protein is that operating with BMP4: BMP4 induces Msx2 expression and in turn, MSX2 controls Bmp4 (Bei and Maas, 1998 ) (Figure 2 ). Indeed, the Msx2 promoter contains a BMP-responsive enhancer element (Brugger et al, 2004 ) and the Bmp4 promoter contains an Msx (1 and 2) responsive element (Wang et al, 2011 ).…”

Section: Msx2: a Key Element Of The Transcriptional Network Determinimentioning

confidence: 99%

MSX2 in ameloblast cell fate and activity

et al. 2015

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While many effectors have been identified in enamel matrix and cells via genetic studies, physiological networks underlying their expression levels and thus the natural spectrum of enamel thickness and degree of mineralization are now just emerging. Several transcription factors are candidates for enamel gene expression regulation and thus the control of enamel quality. Some of these factors, such as MSX2, are mainly confined to the dental epithelium. MSX2 homeoprotein controls several stages of the ameloblast life cycle. This chapter introduces MSX2 and its target genes in the ameloblast and provides an overview of knowledge regarding its effects in vivo in transgenic mouse models. Currently available in vitro data on the role of MSX2 as a transcription factor and its links to other players in ameloblast gene regulation are considered. MSX2 modulations are relevant to the interplay between developmental, hormonal and environmental pathways and in vivo investigations, notably in the rodent incisor, have provided insight into dental physiology. Indeed, in vivo models are particularly promising for investigating enamel formation and MSX2 function in ameloblast cell fate. MSX2 may be central to the temporal-spatial restriction of enamel protein production by the dental epithelium and thus regulation of enamel quality (thickness and mineralization level) under physiological and pathological conditions. Studies on MSX2 show that amelogenesis is not an isolated process but is part of the more general physiology of coordinated dental-bone complex growth.

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“…It has been demonstrated that transcriptional repression by MSX1 occurs in the absence of DNA-binding sites; the repressor function is attributed to multiple domains in the N- and C-terminal regions of MSX136. In silico analysis studies have indicated that missense mutations affecting MH4 in MSX1 alter the encoded 3D structures of the proteins, specifically by destabilizing the helix-turn-helix motif or altering its protein-DNA interactions3738. Moreover in vitro studies have demonstrated that nuclear localization of MSX1 protein is mediated by the homeodomain37.…”

Section: Discussionmentioning

confidence: 99%

“…In silico analysis studies have indicated that missense mutations affecting MH4 in MSX1 alter the encoded 3D structures of the proteins, specifically by destabilizing the helix-turn-helix motif or altering its protein-DNA interactions3738. Moreover in vitro studies have demonstrated that nuclear localization of MSX1 protein is mediated by the homeodomain37.…”

Section: Discussionmentioning

confidence: 99%

Novel human mutation and CRISPR/Cas genome-edited mice reveal the importance of C-terminal domain of MSX1 in tooth and palate development

Mitsui

Yasue

Masuda

et al. 2016

Sci Rep

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Several mutations, located mainly in the MSX1 homeodomain, have been identified in non-syndromic tooth agenesis predominantly affecting premolars and third molars. We identified a novel frameshift mutation of the highly conserved C-terminal domain of MSX1, known as Msx homology domain 6 (MH6), in a Japanese family with non-syndromic tooth agenesis. To investigate the importance of MH6 in tooth development, Msx1 was targeted in mice with CRISPR/Cas system. Although heterozygous MH6 disruption did not alter craniofacial development, homozygous mice exhibited agenesis of lower incisors with or without cleft palate at E16.5. In addition, agenesis of the upper third molars and the lower second and third molars were observed in 4-week-old mutant mice. Although the upper second molars were present, they were abnormally small. These results suggest that the C-terminal domain of MSX1 is important for tooth and palate development, and demonstrate that that CRISPR/Cas system can be used as a tool to assess causality of human disorders in vivo and to study the importance of conserved domains in genes.

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Msx1 Mutations

Cited by 32 publications

References 27 publications

A novel mutation of MSX1 in oligodontia inhibits odontogenesis of dental pulp stem cells via the ERK pathway

A novel mutation of MSX1 in oligodontia inhibits odontogenesis of dental pulp stem cells via the ERK pathway

MSX2 in ameloblast cell fate and activity

Novel human mutation and CRISPR/Cas genome-edited mice reveal the importance of C-terminal domain of MSX1 in tooth and palate development

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