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

Abstract

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.

Phosphorylation of Msx1 promotes cell proliferation through the Fgf9/18-MAPK signaling pathway during embryonic limb development

“…It was recently found that Msx1 plays an important role in human odontogenesis. Specifically, a frame-shift mutation in Msx1 in human dental pulp stem cells weakened the activity of the MAPK signaling pathway and decreased the proliferation of cells, leading to the developmental deficiency of teeth ( 73 ). This mutation disrupted the Msx1 protein at the amino acid residue Met43; therefore, Ser136 was also disrupted.…”

Two novel mutations in MSX1 causing oligodontia

“…It has been demonstrated that the homeodomain is important for the successful interaction of MSX1 with other proteins such as TATA box binding protein (TBP) and distal-less homeobox (DLX) [37,38]. However, the role of MSX1 in human craniofacial and dental development has not been fully elucidated [39].…”

DPSCs Attenuate Experimental Progressive TMJ Arthritis by Inhibiting the STAT1 Pathway

“…Protocols used to acquire human tissues were previously described (Xin et al 2018) and conducted upon obtaining approval from the Ethical Guidelines of Peking University and informed consent from participants (PKUSSIRB-201311103). DPSCs were dissected from the extracted premolars of healthy donors and cultured with alpha modification of Eagle’s medium (containing 15% fetal bovine serum) at 37 °C with 5% CO 2 .…”

“…DPSCs were dissected from the extracted premolars of healthy donors and cultured with alpha modification of Eagle’s medium (containing 15% fetal bovine serum) at 37 °C with 5% CO 2 . DPSCs were identified according to a previously described method (Xin et al 2018), and cells with 3 passages were used.…”