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Gene expression array of brain, mandible and maxilla tissues from P0 FoxO6-/- and wildtype mice

ABSTRACT: FoxO6 is expressed in the brain, craniofacial region and somite, but the precise role of FoxO6 in craniofacial development remain unknown. We found that FoxO6 is expressed specifically in craniofacial tissues and FoxO6-/- mice undergo expansion of the face, frontal cortex, olfactory component and skull. Our gene expression array data demonstrated that Lats1, an important component of Hippo signaling pathway, was decresed in FoxO6-/- mice. Our in vitro and in vivo data further validated that FoxO6 activates Lats1 expression, thereby increasing Yap phosphorylation and activation of Hippo signaling.

ORGANISM(S): Mus musculus

PROVIDER: GSE117013 | GEO | 2018/07/13

REPOSITORIES: GEO

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Lats1/2 control TGF-beta directed EMT in the dorsal cranial neuroepithelium through YAP regulation

Project description:Hippo signaling, an evolutionarily conserved pathway involved in organ size control, has been implicated to play key roles in developmental processes of various tissues, but its role in craniofacial development has not been largely explored. To examine the function of the Hippo signaling kinase cascade, we inactivated Hippo components Lats1 and Lats2 in the cranial neuroepithelium of mouse embryos using a Wnt1CreSOR driver. Double conditional knock out (DCKO) of Lats1/2 resulted in neural tube and craniofacial defects. Lats1/2 DCKO mutant embryos presented a minute head with delayed and defective neural tube closure. Furthermore, neuroepithelial cell polarity and cell integrity were disrupted within the cranial neural tube in Lats1/2 DCKO mutants. Embryonic neural tube RNA-seq revealed increased TGF-beta signaling in absence of Lats1/2. Moreover, markers of epithelial-to-mesenchymal transition (EMT) were upregulated in the cranial neural tube. Notably, modulation of Hippo signaling downstream effectors Yap and Taz prevented neuroepithelial defects, aberrant EMT, and TGF-beta dysregulation caused by Lats1/2 deficiency, indicating that Lats1/2 function via canonical Hippo-Yap pathway. Together, our findings revealed important roles for Hippo signaling kinases in pre-migratory neural crest EMT and migration.

2022-09-05 | GSE182721 | GEO

MH002: FoxO6 is required for Plxna4-mediated neuronal migration during cortical development

Project description:The forkhead transcription factor FoxO6 is prominently expressed during development of the murine neocortex. However, its function in cortical development is as yet unknown. We now demonstrate that cortical development is altered in FoxO6+/- and FoxO6-/- mice, showing migrating neurons halted in the intermediate zone. Using a FoxO6-directed siRNA approach, we substantiate the requirement of FoxO6 for a correct radial migration in the developing neocortex. Subsequent genome-wide transcriptome analysis reveals altered expression of genes involved in cell adhesion, axon guidance, and gliogenesis upon silencing of FoxO6 We then show that FoxO6 binds to DAF-16-binding elements in the Plexin A4 (Plxna4) promoter region and affects Plxna4 expression. Finally, ectopic Plxna4 expression restores radial migration in FoxO6+/- and siRNA-mediated knockdown models. In conclusion, the presented data provide insights into the molecular mechanisms whereby transcriptional programs drive cortical development.

2016-11-11 | GSE71954 | GEO

Gene expression array of brain, mandible and maxilla tissues from P0 FoxO6-/- and wildtype mice

Project description:Gene expression array of brain, mandible and maxilla tissues from P0 FoxO6-/- and wildtype mice

| PRJNA480854 | ENA

FoxO6 regulates memory consolidation and synaptic function.

Project description:We used microarrays to assess gene expression differences in the hippocampus between FoxO6 mutant and wild-type siblings before (basal) or after novel object learning.

2012-11-08 | GSE42097 | GEO

Resolving the function of FoxO6 during Somatic Cell Reprogramming by RNA-seq

Project description:Purpose: Next-generation sequencing (NGS) has revolutionized systems-based analysis of cellular pathways. The goals of this study are to explore the function of FoxO6 in reprogramming system Methods: The mRNA profiles of OKS induced reprogramming systems with and without FoxO6 were generated by deep sequencing.

2020-12-31 | GSE161057 | GEO

The Hippo pathway kinase LATS1 scaffolds Beclin1 in autophagy regulation in hepatocellular carcinoma

Project description:Autophagy perturbation represents an emerging therapeutic strategy in cancer. The mammalian Hippo pathway is an evolutionary conserved tumor suppressive network, where the kinases LATS1/2 phosphorylate and inactivate oncogenic YAP/TAZ. Here, we demonstrated a pro-survival role of LATS1, but not LATS2, in hepatocellular carcinoma cells in response to sorafenib, a standard care of advanced HCC. Transcriptomic analysis revealed a restrictive role of LATS1 in autophagy regulation in HCC cells. Further, we found that the autophagy regulation by LATS1 was independent of its kinase activity. Instead, LATS1 stabilized autophagy core-machinery component Beclin 1 via promoting a non-canonical form of K27-linked ubiquitination, and consequently, inactive Beclin 1 self-dimer, in a E3 ligase NEDD4 dependent manner. Our study highlights a functional diversity between LATS1 and LATS2 and uncovers a scaffolding role of LATS1 in mediating a cross-talk between Hippo signalling and autophagy in HCC and therapy response.

2019-11-13 | GSE117116 | GEO

Targeting upstream Hippo-pathway kinases releases the scaffolder WWC1 to promote synaptic plasticity and long-term memory in mice

Project description:The localization, number, and function of postsynaptic AMPA-type glutamate receptors (AMPARs) are crucial for synaptic plasticity, a cellular correlate for learning and memory. The Hippo pathway member WWC1 is an important component of AMPAR hetero-protein complexes. However, genetic analysis suggests that the availability of WWC1 is constrained by its interaction with the Hippo kinases LATS1 and LATS2 (LATS1/2). Here, we explored the biochemical regulation of this interaction. A proteome-wide analysis of kinase inhibition in SH-SY5Y neuroblastoma cell line using the kinobead assay identified the upstream kinases MST1/2 as two major targets of the small molecule inhibitor XMU-MP1 (hereafter, MSTi)and Luteolin.Upon pharmacological inhibition of MST1/2 in male mice and human brain organoids WWC1 dissociated from LATS1/2, resulting in increased abundance of WWC1 in AMPAR complexes. Moreover, MSTi enhanced synaptic transmission in mouse hippocampal brain slices, and improved cognition in healthy male mice and in male mouse models of Alzheimer’s disease and ageing. Thus, blocking WWC1-LATS1/2 binding might be explored for development as cognitive enhancers.

2024-05-03 | PXD050351 | Pride

Downregulation of LATS kinases alters p53 to promote cell migration

Project description:p53 is a pivotal tumor suppressor and a major barrier against cancer. We now report that silencing of the Hippo pathway tumor suppressors LATS1 and LATS2 in non-transformed mammary epithelial cells reduces p53 phosphorylation and increases its association with the p52 NF-?B subunit. Moreover, it partly shifts p53âs conformation and transcriptional output towards a state resembling cancer-associated p53 mutants, and endow p53 with the ability to promote cell migration. Notably, LATS1 and LATS2 are frequently downregulated in breast cancer; we propose that such downregulation might benefit cancer by converting p53 from a tumor suppressor into a tumor facilitator. MCF10A cells transfected with siRNA against LATS1/2 alone, p53 alone or LATS1/2 and p53 together. Two independent MCF10A batches provided biological replicates

2015-12-11 | E-GEOD-74493 | biostudies-arrayexpress

Transcription profiling by array of human MCF10A cells expressing YAP to identify the targets of the YAP oncogene

Project description:YAP is an oncogene and an inducer of Epithelial-to-Mesenchymal Transition (EMT). We used microarrays to detail the global program of gene expression to identify YAP target genes. PUBLICATION ABSTRACT:; The Hippo pathway defines a novel signaling cascade regulating cell proliferation and survival in Drosophila, which involves the negative regulation of the transcriptional coactivator Yorkie by the kinases Hippo and Warts. We have recently shown that the human ortholog of Yorkie, YAP, maps to a minimal amplification locus in mouse and human cancers, and that it mediates dramatic transforming activity in MCF10A primary mammary epithelial cells. Here we show that LATS proteins (mammalian orthologs of Warts) interact directly with YAP in mammalian cells and that ectopic expression of LATS1, but not LATS2, effectively suppresses the YAP phenotypes. Furthermore, shRNA-mediated knockdown of LATS1 phenocopies YAP overexpression. Since this effect can be suppressed by simultaneous YAP knockdown, it suggests that YAP is the primary target of LATS1 in mammalian cells. Expression profiling of genes induced by ectopic expression of YAP or by knockdown of LATS1 reveals a subset of potential Hippo pathway targets implicated in epithelial-to-mesenchymal transition (EMT), suggesting that this is a key feature of YAP signaling in mammalian cells. Experiment Overall Design: MCF10A cells were infected with retrovirus constructs (vector or YAP) and puromycin was used to select for transduced cells. Cells were split and grown to ~60-75%% confluency at which point they were harvested for RNA. Vector vs. YAP comparison was done in duplicate.

2008-06-11 | E-GEOD-10196 | biostudies-arrayexpress

RNA-seq of ATM-knockout human embryonic stem-cells (h-pES10) treated with the LATS1/2 inhibitor Lats-IN-1 (TRULI) for 24 h against untreated cells

Project description:LATS1/2 are canonical Hippo signaling pathway components. Our genome-wide screen indicated a synthetic viable effect of Hippo pathway inhibition in ATM-depleted human embryonic and neural progenitor cells. This experiment was designed in order to get mechanistic insights regarding the molecular effect of Hippo pathway inhibition on ATM-knockout cells. Such chemical inhibition could potentially be used as a means to impede Ataxia-Telangiectasia-related neurodegeneration. Experimental procedure: 2 clones of ATM-knockout h-pES10 cells were plated on 6 well plates with MEFs feeder layer. 1 d after plating, medium was replaced with standard medium (as control) or medium containing 10 µM of LATS1/2 inhibitor, TRULI (Lats-IN-1) for 24 h. Cells were then harvested, total RNA was extracted, libraries for RNA sequencing were generated and sequenced. Total reads were mapped to human GRCh38 reference genome, and to mouse GRCm38 using STAR package. XenofilteR package in R was used to filter out mouse-originated reads. Count tables and differential analysis were performed using EdgeR package in R.

2024-01-10 | E-MTAB-12600 | biostudies-arrayexpress

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