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Multimodal spatiotemporal transcriptomic resolution of embryonic palate osteogenesis

ABSTRACT: Multimodal spatiotemporal transcriptomic resolution of embryonic palate osteogenesis

PROVIDER: PRJNA845449 | ENA |

REPOSITORIES: ENA

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Multimodal spatiotemporal transcriptomic resolution of embryonic palate osteogenesis [Spatial Transcriptomics]

Project description:Multimodal spatiotemporal transcriptomic resolution of embryonic palate osteogenesis [Spatial Transcriptomics]

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Multimodal spatiotemporal transcriptomic resolution of embryonic palate osteogenesis [multiome RNAseq+ATACseq]

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Multimodal spatiotemporal transcriptomic resolution of embryonic palate osteogenesis [Spatial Transcriptomics]

Project description:The terminal differentiation of osteoblasts and subsequent formation of bone marks an important phase in palate development that leads to the separation of the oral and nasal cavities. While the morphogenetic events preceding palatal osteogenesis are well explored, major gaps remain in our understanding of the molecular mechanisms driving the formation of this bony union of the fusing palate. Through bulk, single-nucleus, and spatially resolved RNA-sequencing analyses of the developing secondary palate, we identify a shift in transcriptional programming between embryonic days 14.5 and 15.5 pinpointing the onset of osteogenesis. We define spatially restricted expression patterns of key osteogenic marker genes that are differentially expressed between these developmental timepoints. Finally, we identify genes in the palate highly expressed by palate nasal epithelial cells, also enriched within palatal osteogenic mesenchymal cells. This investigation provides a relevant framework to advance palate-specific diagnostic and therapeutic biomarker discovery.

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Multimodal spatiotemporal transcriptomic resolution of embryonic palate osteogenesis.

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Project description:This SuperSeries is composed of the SubSeries listed below.

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Multimodal transcriptomic profiling of the embryonic palate enables novel in utero cleft therapy [scRNA-Seq]

Project description:Cleft palate is a common disorder of development resulting from failure of growth, migration, elevation, and osteogenic fusion of embryonic cranial neural crest-derived palatal shelves. Despite progress in recent decades, the molecular pathways involved in this failure are not well understood. Here, we present a multimodal, spatiotemporal transcriptomic profiling of the developing palate through integrated, unbiased single-cell and bulk RNA-sequencing and multiplexed in situ mRNA mapping of osteogenic cell lineages. We then show that loss of Pax9, a critical transcription factor orchestrator of Wnt signaling in palate development, results in increased expression of sclerostin (Sost), a known antagonist of Wnt signaling. Finally, we reveal that a single dose of sclerostin-neutralizing monoclonal antibody restores Wnt signaling and corrects cleft palate defects in utero in Pax9-/- mouse embryos.

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Multimodal transcriptomic profiling of the embryonic palate enables novel in utero cleft therapy [bulk RNA-Seq]

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Ectopic Hedgehog signalling causes cleft palate and defective osteogenesis

Project description:In this study, we have investigated the molecular basis of Shh signalling during development of the secondary palate and how CNCC patterning and fate is influenced by the Shh signalling network. Using a gain-of-function mouse model to activate Smoothened (R26SmoM2) signalling in the palatal mesenchyme (Osr2-IresCre), we demonstrate ectopic Hh-Smo signalling results in fully penetrant cleft palate, disrupted oral-nasal patterning and defective palatine bone formation. We show that a series of Fox transcription factors, including the novel direct target Foxl1, function downstream of Hh signalling in the secondary palate. Furthermore, we demonstrate that Wnt/BMP antagonists, in particular Sostdc1, are positively regulated by Hh signalling, concomitant with down-regulation of key regulators of osteogenesis and BMP signalling effectors. Microarray analysis was performed on excised palatal shelves from Osr2-IresCre+/- (wild-type) and Osr2-IresCre;Smo+/M2 (mutant) embryos at embryonic day (E)13.5. Osr2-IresCre (PMID:17941042) and R26SmoM2 (PMID:15107405) mice have been described previously.

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Shox2 regulates osteogenesis and patterns the hard palate during palatogenesis

Project description:Shox2 regulates osteogenesis and patterns the hard palate during palatogenesis

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