Organ of Corti size is governed by Yap/Tead-mediated progenitor self-renewal
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ABSTRACT:
ORGANISM(S): Mus musculus
PROVIDER: GSE149254 | GEO | 2020/04/24
REPOSITORIES: GEO
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Project description:Precise control of organ growth and patterning is executed through a balanced regulation of progenitor self-renewal and differentiation. In the auditory sensory epithelium-the organ of Corti-progenitor cells exit the cell cycle in a coordinated wave between E12.5 and E14.5 before the initiation of sensory receptor cell differentiation, making it a unique system for studying the molecular mechanisms controlling the switch between proliferation and differentiation. Here we identify the Yap/Tead complex as a key regulator of the self-renewal gene network in organ of Corti progenitor cells. We show that Tead transcription factors bind directly to the putative regulatory elements of many stemness- and cell cycle-related genes. We also show that the Tead coactivator protein, Yap, is degraded specifically in the Sox2-positive domain of the cochlear duct, resulting in down-regulation of Tead gene targets. Further, conditional loss of the Yap gene in the inner ear results in the formation of significantly smaller auditory and vestibular sensory epithelia, while conditional overexpression of a constitutively active version of Yap, Yap5SA, is sufficient to prevent cell cycle exit and to prolong sensory tissue growth. We also show that viral gene delivery of Yap5SA in the postnatal inner ear sensory epithelia in vivo drives cell cycle reentry after hair cell loss. Taken together, these data highlight the key role of the Yap/Tead transcription factor complex in maintaining inner ear progenitors during development, and suggest new strategies to induce sensory cell regeneration.
| S-EPMC7306825 | biostudies-literature
Project description:Organ of Corti size is governed by Yap/Tead-mediated progenitor self-renewal
| PRJNA627734 | ENA
Project description:The genomic regulatory programs that underlie human organogenesis are poorly understood. Human pancreas development, in particular, has pivotal implications for pancreatic regeneration, cancer, and diabetes. We have now created maps of transcripts, active enhancers, and transcription factor networks in pancreatic multipotent progenitors obtained from human embryos, or derived in vitro from human embryonic stem cells. This revealed that artificial progenitors recapitulate salient transcriptional and epigenomic features of their natural counterparts. Using this resource, we show that TEAD1, a transcription factor controlled by Hippo signaling, is a core component of the combinatorial code of pancreatic progenitor enhancers. TEAD thus activates genes encoding regulators of signaling pathways and stage-specific transcription factors that are essential for normal pancreas development. Accordingly, chemical and genetic perturbations of TEAD and its coactivator YAP inhibited expression of known regulators such as FGFR2 and SOX9, and suppressed the proliferation and expansion of mouse and zebrafish pancreatic progenitors. These findings provide a resource of active enhancers and transcripts in human pancreatic multipotent progenitors, and uncover a central role of TEAD and YAP as signal-responsive regulators of the transcriptional program of early pancreas development.
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Project description:During placentation, placental cytotrophoblast cells differentiate into syncytiotrophoblast cells and extravillous trophoblast cells. In placenta, the expression of various genes is regulated by the Hippo pathway through the transcriptional coactivator YAP/TAZ-TEAD activity. To examine the effect of YAP/TAZ and/or TEAD on trophoblast differentiation, knockdown experiments were performed. Microarray analysis were performed to identify YAP/TAZ and/or TEAD target genes in human trophoblast.
2022-07-17 | GSE182900 | GEO
Project description:YAP1 (Yes-associated protein 1) is transcriptional co-activator that partners with the TEAD family of transcription factors to regulate gene expression. Increased YAP-TEAD activity is strongly implicated in the development, progression, and metastasis of several cancer types including melanoma, but the YAP-TEAD target genes that are responsible for YAP-TEAD-dependent melanoma progression and metastasis are largely unknown. To identify YAP-TEAD regulated genes in metastatic melanoma cells we used RNA-sequencing to compare gene expression in control A375 human melanoma cells to A375 cells expressing mutant forms of YAP with increased transcriptional activity due to the mutation of LATS inhibitory phosphorylation sites (YAPS127A or YAPS127A,S381A). To determine which YAP-dependent gene expression changes are mediated by TEADs we also included a mutant form of YAP that is unable to bind TEADS (YAPS94A,S127A).
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Project description:The microRNA miR-96 is important for hearing; mutations in the seed region result in dominant progressive hearing loss in mice and humans. Mir96 is expressed in the sensory hair cells of the organ of Corti along with Mir182 and Mir183. miR-96 is a master regulator of hair cell development, controlling many genes in the organ of Corti, but the role of miR-182 and miR-183 in the hair cells is unknown. We carried out RNA-seq on mice carrying a knockout allele of Mir182, and mice carrying a double knockout allele of Mir183 and Mir96 (Mir183/96). RNA was extracted from the organ of Corti from P4 homozygotes and sex-matched wildtype littermates. Strand-specific libraries were prepared using the NuGEN Ovation Mouse RNA-Seq System 1-16 kit and sequenced on an Illumina HiSeq 2500 machine as paired-end 125bp reads.
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Project description:Cre recombinase-mediated conditional knockout of floxed Dicer1 alleles causes depletion of small RNAs including microRNAs, which function to repress target mRNA expression by inhibiting translation and/or stimulating mRNA degradation. We used microarrays to examine gene expression in apical versus basal organ of Corti from the cochleae of control and mutant mice in which Dicer1 was deleted and microRNAs were depleted specifically in sensory hair cells by Atoh1 promoter-driven Cre recombinase expression. Each biological replicate represents the combined apical or combined basal segments of organ of Corti from both cochleae of a single mouse. Two biological replicates for apical and basal organ of Corti from Dicer1 conditonal knockout and littermate controls were collected for RNA extraction and microarray analysis.
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