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Next Generation Sequencing Identifies Hoxa1 and Hoxc13 as Downstream Targets of Yap in Mouse Epithelial Tissues

ABSTRACT: The goals of this study are to identify in vivo downstream targets of Yap through NGS-derived tooth germ transcriptome profiling. The mRNA profiles of wild-type, Yap conditional knockout (CKO) and YAP transgenic (Tg) mouse tooth germs at embryonic day 14.5 were generated by deep sequencing using Illumina Hiseq2000. The sequence reads that passed quality filters were analyzed at the transcript isoform level via DNAnexus. The validation was performed through qRT–PCR and in situ hybrydization. A set of Hox genes were differentially expression in Yap CKO and YAP Tg mouse tooth germs, demonstating concurrent expression changes with Yap transcripts. This study provides a platform to systematically identify in vivo downstream targets of genes of interest.

ORGANISM(S): Mus musculus

PROVIDER: GSE65524 | GEO | 2015/02/21

SECONDARY ACCESSION(S): PRJNA274271

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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Next Generation Sequencing Identifies Hoxa1 and Hoxc13 as Downstream Targets of Yap in Mouse Epithelial Tissues

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