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Integrating single-cell RNA-sequencing and transcriptomic data reveals essential genes for tooth development processes

ABSTRACT: The organ development is dictated by the genes preferentially expressed in tissue or cell types uniquely. The clarification of gene expression profile and identification of specific genes in organ provide detailed understanding of organogenesis. Toward this purpose, the genome-wide analysis is a growing powerful tool for understanding development processes in organogenesis. Tooth is composed from enamel, dentin and cementum and these tissues are identical from other organs. The tooth-forming cell types are therefore unique and have complexed organization. The mechanisms of signal induction during tooth development is complicated because of the function of each cell types are still unclear. Previously, we performed the CAGE (Cap Analysis of Gene Expression) using mouse tooth germ to identify the genes preferentially expressed in tooth. The CAGE has advantage in quantification because it counts short reads of 5’ end without the bias of transcript length. Single-cell RNA-sequence (scRNA-seq) is a suitable tool revealing gene expression of each cells. The fundamental question of this study is how we can identify the tooth-specific and cell-type specific genes. In this study, we approach this using combination of scRNA-seq and CAGE (Cap Analysis of Gene Expression) as bioinformatics analyses. We obtained the scRNA-seq datasets of 12,212 cells from postnatal-day (P) 1 mouse molars, and the CAGE-seq datasets from P1 molars. scRNA-seq analysis revealed the spatio-temporal expression of tooth-related genes and CAGE determined whether these genes are truly tooth-specific or are expressed in ubiquitously. Furthermore, we identified candidate genes as novel tissue- and cell type- specific markers. Our results show that the integration of scRNA-seq and CAGE-seq improves the highlight genes important for tooth development from numerous gene profiles. These findings contribute resolving the mechanism of tooth development and establish the basis of tooth regeneration in future.

ORGANISM(S): Mus musculus

PROVIDER: GSE167989 | GEO | 2021/12/06

REPOSITORIES: GEO

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Project description:Previous studies have suggested that Bmp4 is a key Msx1-dependent mesenchymal odontogenic signal for driving tooth morphogenesis through the bud-to-cap transition. Whereas the bud stage tooth developmental arrest in Msx1-/- mutant mice was accompanied by reduction in mesenchymal Bmp4 mRNA expression, we show that depleting functional Bmp4 mRNAs in the tooth mesenchyme, through neural crest-specific gene inactivation in Bmp4f/f;Wnt1Cre mice, caused mandibular molar developmental arrest at the bud stage but allowed maxillary molars and incisors to develop to mineralized teeth. We show that the Wnt inhibitors Dkk2 and Wif1 were much more abundantly expressed in the mandibular than maxillary molar mesenchyme in wildtype embryos and that Dkk2 expression was significantly unregulated in the tooth mesenchyme in Bmp4f/f;Wnt1Cre embryos. In addition, expression of Osr2, which encodes a zinc finger protein that antagonizes Msx1-mediated activation of odontogenic mesenchyme, is significantly upregulated in the molar mesenchyme in Bmp4f/f;Wnt1Cre embryos. Msx1 heterozygosity enhanced maxillary molar developmental defects whereas Osr2 heterozygosity rescued mandibular first molar morphogenesis in Bmp4f/f;Wnt1Cre mice. Moreover, in contrast to complete lack of supernumerary tooth initiation in Msx1-/-Osr2-/- mutant mice, Osr2-/-Bmp4f/f;Wnt1Cre compound mutant mice exhibit formation and subsequent arrest of supernumerary tooth germs that correlated with down regulation of Msx1 expression in the tooth mesenchyme. Taken together, our data indicate that, while reduction in mesenchymal Bmp4 expression alone could not account for the tooth bud arrest phenotype in Msx1-/- mutant mice, Bmp4 signaling synergizes with Msx1 and antagonizes Osr2 to activate mesenchymal odontogenic activity to drive tooth morphogenesis and sequential tooth formation. E13.5 mouse embryos tooth germs were microdissected by laser capture microdissection (LCM), and the mandibular molar and maxillary molar were separated. 3 pairs of control and mutant samples were pooled for the RNA extraction.

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Integrating single-cell RNA-sequencing and transcriptomic data reveals essential genes for tooth development processes

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