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The Pitx2:miR-200c/141:noggin pathway regulates BMP signaling and ameloblast differentiation

ABSTRACT: The mouse incisor is a remarkable tooth that grows throughout the animal’s lifetime. This continuous renewal is fueled by epithelial stem cells that give rise to ameloblasts, which generate enamel, and little is known about the function of specific miRNAs in this process. Here we describe the role of a novel Pitx2:miR-200c/141:Noggin regulatory pathway in dental epithelial cell differentiation. miR-200c repressed noggin, an antagonist of Bmp signaling. Pitx2 expression caused an up-regulation of miR-200c and chromatin immunoprecipitation (ChIP) assays revealed endogenous Pitx2 binding to the miR-200c/141 promoter. A positive feedback loop was discovered between miR-200c and Bmp signaling. miR-200c/141 induced expression of E-cadherin and the dental epithelial cell differentiation marker, amelogenin. In addition, miR-203 expression was activated by endogenous Pitx2 and targeted the Bmp antagonist Bmper to further regulate Bmp signaling. miR-200c/141 knockout mice showed defects in enamel formation with decreased E-cadherin and amelogenin expression and increased noggin expression. Our in vivo and in vitro studies reveal a multistep transcriptional program involving the Pitx2:miR-200c/141:Noggin regulatory pathway that is important in epithelial cell differentiation and tooth development.

ORGANISM(S): Mus musculus

PROVIDER: GSE48583 | GEO | 2013/07/09

SECONDARY ACCESSION(S): PRJNA210751

REPOSITORIES: GEO

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The Pitx2:miR-200c/141:noggin pathway regulates BMP signaling and ameloblast differentiation

Project description:The mouse incisor is a remarkable tooth that grows throughout the animalM-bM-^@M-^Ys lifetime. This continuous renewal is fueled by epithelial stem cells that give rise to ameloblasts, which generate enamel, and little is known about the function of specific miRNAs in this process. Here we describe the role of a novel Pitx2:miR-200c/141:Noggin regulatory pathway in dental epithelial cell differentiation. miR-200c repressed noggin, an antagonist of Bmp signaling. Pitx2 expression caused an up-regulation of miR-200c and chromatin immunoprecipitation (ChIP) assays revealed endogenous Pitx2 binding to the miR-200c/141 promoter. A positive feedback loop was discovered between miR-200c and Bmp signaling. miR-200c/141 induced expression of E-cadherin and the dental epithelial cell differentiation marker, amelogenin. In addition, miR-203 expression was activated by endogenous Pitx2 and targeted the Bmp antagonist Bmper to further regulate Bmp signaling. miR-200c/141 knockout mice showed defects in enamel formation with decreased E-cadherin and amelogenin expression and increased noggin expression. Our in vivo and in vitro studies reveal a multistep transcriptional program involving the Pitx2:miR-200c/141:Noggin regulatory pathway that is important in epithelial cell differentiation and tooth development. Lower incisors of 3-5 P0 WT and Pitx2-Cre;Dicer1 cKO mices from same litter were dissected and combined for RNA extraction. Two different litters were analyzed. For mRNA microarray, CodeLink Mouse Whole Genome chips (Applied Microarrays) were used according to manufacturerM-bM-^@M-^Ys instruction (done at Genomics Core of TAMU). miRNA from P0 Lower Incisor ameloblast and cervical loops.

2013-07-09 | E-GEOD-48583 | biostudies-arrayexpress

Mus musculus

Project description:The Pitx2:miR-200c/141:noggin pathway regulates BMP signaling and ameloblast differentiation

| PRJNA210751 | ENA

Single cell transcriptional profiling of mouse molar and incisor tooth assembloids

Project description:Throughout the various stages of tooth development, reciprocal epithelial-mesenchymal interactions are the driving force, for instance crucially involved in the differentiation of mature enamel-forming ameloblasts and dentin-producing odontoblasts. Here we established mouse tooth ‘assembloids’, comprised of tooth organoid-derived dental epithelial cells (from mouse molars and incisors) cultured together with molar dental pulp stem cells (DPSCs), to mimic these developmental interactions. Assembloids from both tooth types were grown both in basal- and differentiation-inducing conditions. Single cell transcriptomics analysis was applied to in detail characterize and validate the newly developed mouse tooth assembloid model and evaluate the induced differentiation processes.

2023-04-19 | E-MTAB-12544 | biostudies-arrayexpress

Single-cell RNA-sequencing from mouse incisor reveals dental epithelial cell-type specific genes

Project description:Dental epithelial stem cells give rise to all dental epithelial cell types, inner enamel epithelium, outer enamel epithelium, ameloblasts, stratum intermedium and stellate reticulum to form enamel. These all types of epithelial cells have distinct roles and are essential for enamel formation. These cell types are conventionally classified by their cell shape, however, the transcriptome and biological roles of each cell types are not fully understood. Here, we used single-cell RNA-sequencing to clarify the heterogeneity of dental epithelial cell types. Unbiased clustering of 6260 single-cells from post-natal day 7 mouse incisors are classified into 4 dental epithelial and 2 mesenchymal populations; 2 clusters of ameloblast, IEE/OEE and SI/SR clusters. Secretory-stage of ameloblasts were divided into Dspp+ or Ambn+ ameloblast. Pseudo-time analysis indicated that Dspp+ ameloblast differentiate into Ambn+ ameloblast. Further, Dspp and Ambn would be stage-specific markers of ameloblast. Gene Ontology (GO) analyses of each clusters indicate potent roles of cell types; OEE in regulation of tooth size and SR in transport of nutrition. Moreover, we identified novel dental epithelial cell marker genes, Pttg1, Atf3, Cldn10 and Krt15. These results provide a resource of transcriptome data in dental cells and contribute further molecular analyses of enamel formation.

2020-09-23 | GSE146855 | GEO

Adult Dental Epithelial Stem Cell-Derived Organoids Deposit Hydroxylapatite Biomineral

Project description:Ameloblasts are specialized cells derived from the dental epithelium that produce enamel, a hierarchically structured tissue comprised of highly elongated hydroxylapatite (OHAp) crystallites. Because enamel is acellular and has limited capacity to heal, regenerative technologies are highly desirable, yet have remained largely out of reach. This is in part due to the challenges of synthesizing crystallites with similar properties and assembling them in a mechanically robust structure. Herein, we demonstrate the ability to generate mineralizing dental epithelial organoids (DEOs) from adult dental epithelial stem cells (aDESCs) isolated from mouse incisor tissues. DEOs expressed ameloblast markers, could be maintained for more than five months (11 passages) in vitro in media containing modulators of Wnt, Egf, Bmp, Fgf and Notch signaling pathways, and were amenable to cryostorage. When implanted underneath murine kidney capsules, organoids produced OHAp crystallites similar in composition, size, and shape to mineralized dental tissues, including some enamel-like elongated crystals. DEOs are thus a powerful in vitro model for the development of the dental epithelium and enamel, and an important first step towards regrowth or replacement of enamel.

2023-11-18 | GSE220686 | GEO

G-protein coupled receptor Gpr115 (Adgrf4) is required for enamel mineralization mediated by ameloblasts

Project description:Dental enamel, the hardest tissue in the human body, is derived from dental epithelial cell ameloblast-secreted enamel matrices. Enamel mineralization occurs in a strictly synchronized manner along with ameloblast maturation in association with ion transport and pH balance, and any disruption of these processes results in enamel hypomineralization. G-protein coupled receptors (GPCRs) function as transducers of external signals by activating associated G-proteins and regulate cellular physiology. Tissue-specific GPCRs play important roles in organ development, though their activities in tooth development remains poorly understood. The present results show that the adhesion-GPCR Gpr115 (Adgrf4) is highly and preferentially expressed in mature ameloblasts and plays a crucial role during enamel mineralization. To investigate the in vivo function of Gpr115, knockout (Gpr115-KO) mice were created and found to develop hypo-mineralized enamel, with a larger acidic area due to the dysregulation of ion composition. Transcriptomic analysis also revealed that deletion of Gpr115 disrupted pH homeostasis and ion transport processes in enamel formation. In addition, in vitro analyses using the dental epithelial cell line Cervical Loop-Derived Dental Epithelial (CLDE) cell demonstrated that Gpr115 is indispensable for the expression of carbonic anhydrase 6 (Car6), which has a critical role in enamel mineralization. Furthermore, an acidic condition induced Car6 expression under the regulation of Gpr115 in CLDE cells. Thus, we concluded that Gpr115 plays an important role in enamel mineralization via regulation of Car6 expression in ameloblasts. The present findings indicate a novel function of Gpr115 in ectodermal organ development and clarify the molecular mechanism of enamel formation.

2020-08-31 | GSE155641 | GEO

MicroRNA-200c/141 confines ERα activity and expression pattern by targeting Ccnd1 [bulk RNA-seq]

Project description:ERα is one of the most important transcription factors and therapeutic targets in breast cancer. The patterns of ERα expression in normal breast tissue and cancerous lesions are strikingly different. What drives the change of ERα pattern during lesions formation remains unclear. Here, we describe a novel regulatory mechanism through which miR-200c/141 regulates the level as well as the distribution of ERα in the mammary gland. miR-200c/141 is specifically expressed in luminal cells. Luminal-deletion of miR-200c/141 (miR-cKO) leads to a drastic expansion of ERα+ cell proportion. Single cell RNAseq reveals that miR-cKO generates aberrant luminal subpopulations with increased proliferative and anti-apoptotic features. In vivo lineage tracing of ER- luminal cells demonstrates that miR-200c/141 deletion can convert ER- cells into ER+ cells, which contribute partly to the increase of ERα+ luminal cells. Mechanistic study identifies Ccnd1 as a novel target of miR-200c/141 . Upon miR-200c/141deletion, elevated Ccnd1 level corroborates ERα transcriptional activation, leads to enhanced ERα signaling activity, consequently increased transcription of ERα coding gene Esr1 through self-activation at promoter E1. Our findings reveal a new miR-200c/141-Ccnd1-ERα axis, and provide new molecular insights into how miR-200c/141-Ccnd1 enforces the lineage barrier between ER- and ER+ luminal cells, and what drives the change of ERα expression pattern.

2021-05-05 | GSE173815 | GEO

MicroRNA-200c/141 confines ERα activity and expression pattern by targeting Ccnd1 [single-cell RNA-seq]

2021-05-05 | GSE173816 | GEO

TALEN-based knockout of mir-141 and mir-200c in SK-BR-3 cells

Project description:We used transcription activator-like effector nucleases (TALENs) to generate knockout cells for two related microRNAs (miRNAs), mir-141 and mir-200c, which belong to the deeply conserved mir-200 family. By carrying out deep sequencing, we identified the target genes of each miRNA. Interestingly, miR-141 and miR-200c, despite their overall similarity, suppressed largely non-overlapping groups of targets. Analysis of global mRNA level change in mir-141 and mir-200c knockout compared to wild type cells

2013-09-27 | E-GEOD-51217 | biostudies-arrayexpress

RNA sequencing of RipmiR-141~200c and RipmiR-141~200c Zeb1200M islets

Project description:We performed RNA sequencing of islets of Langerhans isolated from RipmiR-141~200c and RipmiR-141~200c Zeb1200M mice to determine the transcriptomic effects of mutating miR-200 binding sites in the endogenous Zeb1 3'UTR of mice in which miR-141~200c is overexpressed under the rat insulin promoter (RIP).

2022-04-30 | E-MTAB-10537 | biostudies-arrayexpress

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