Lats1/2 depletion in male sertoli cells
Ontology highlight
ABSTRACT:
ORGANISM(S): Mus musculus
PROVIDER: GSE243216 | GEO | 2024/04/22
REPOSITORIES: GEO
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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
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
Project description:In order to understand whether sole Cre recombinase expression has an effect on stress signalling pathways and the peroxisomal or other subcellular compartments, we have analyzed total RNA isolated from Sertoli cell cultures of anti-Müllerian-hormone (AMH)-Cre/wild-type and wild-type/wild-type C57BL/6J mouse testes using microarrays.
2012-01-01 | GSE28307 | GEO
Project description:Lats1/2 kinases are the core Hippo pathway kinases. In this study, we use RNAseq to analyze the gene expression profiles of adult mouse uveal tract cells and mouse uveal melanoma generated by Lats1/2 deletion induced by AAV-based Cre injection into mouse uveal tract.
2020-11-10 | GSE115181 | GEO
Project description:Lats1 and Lats2 are the mediators of the Hippo pathway that regulates tissue growth and proliferation. Lats1 and Lats2 kinases share 85% sequence identity in the kinase domain. However, their non-kinase regions at the N-terminus are distinct except for Lats conserved domain 1 (LCD1) and LCD2, suggesting that their N-terminal regions are important for Lats1/2-specific functions. In this study, we generated Lats1 knockout mice disrupting the N-terminal region containing LCD1 (Lats1M-NM-^TN/M-NM-^TN). We show that some Lats1M-NM-^TN/M-NM-^TN mice were born safely and grew normally. However, mouse embryonic fibroblasts (MEFs) from Lats1M-NM-^TN/M-NM-^TN mice displayed drastic defects in mitosis, showing enhanced centrosome overduplication, chromosomal misalignment, multipolar spindle formation, chromosome bridging, and cytokinesis failure. Moreover, they displayed accelerated cell cycle and cell growth bypassing a cell-cell contact inhibition like tumor cells, and exhibited anchorage independent growth. Indeed, Lats1M-NM-^TN/M-NM-^TN MEFs produced tumors in nude mice after subcutaneous injection, although the tumor growth rate was much slower than ordinary cancer cells. Furthermore, Yap, the key transcriptional co-activator in the Hippo pathway, was overexpressed and retained stable in Lats1M-NM-^TN/M-NM-^TN MEFs under high cell density, and expression of Lats2 mRNA were down-regulated. Total RNAs were extracted from MEFs under high or low cell density using miRNeasy extraction kit (Qiagen). A Dye-swapped experiment was performed by hybridizing complimentary RNA (cRNA) labeled with either Cyanine (Cy) -3 or Cy-5 (Perkin-Elmer) onto Whole Mouse Genome Oligo Microarray (G4122F; Agilent Technologies). Co-hybridizations were performed and data from Cy3 or Cy5 channels were analyzed as normalized signal intensities rather than as log ratios corresponding to each array.
2012-12-17 | E-GEOD-37871 | biostudies-arrayexpress
Project description:The Hippo pathway directs cell differentiation during organogenesis, in part by restricting proliferation. How Hippo signaling maintains a proliferation-differentiation balance in developing tissues and its underlying molecular targets are poorly understood. Our study shows that Hippo suppresses NFκB signaling in pancreatic progenitors to permit cell differentiation and developmental progression. We found that pancreas-specific Lats1/2 kinase deletion (Lats1/2PanKO) from mouse progenitor epithelia results in failure to differentiate 3 key pancreatic lineages: acinar, ductal, and endocrine. We performed an unbiased transcriptome analysis to query the differentiation defects in Lats1/2PanKO. This analysis revealed increased NFκB activator expression, including the pantetheinase Vanin1 (Vnn1). Through in vivo and ex vivo studies, we show that VNN1 activates a detrimental cascade of processes in Lats1/2PanKO epithelium, whereby 1) NFκB activation and 2) initiation of epithelial-to-mesenchymal transition (EMT) together override normal differentiation. We show that exogenous stimulation of VNN1 or NFκB can also trigger this cascade in WT pancreatic progenitors. These findings show that pancreas development requires active suppression of NFκB by LATS1/2 kinases to restrain a cell-autonomous transcriptional program and thereby allow for differentiation.
2019-06-21 | GSE126551 | GEO
Project description:In order to understand whether sole Cre recombinase expression has an effect on stress signalling pathways and the peroxisomal or other subcellular compartments, we have analyzed total RNA isolated from Sertoli cell cultures of anti-Müllerian-hormone (AMH)-Cre/wild-type and wild-type/wild-type C57BL/6J mouse testes using microarrays. The Sertoli cells were isolated from individual 14 day-old mice and were cultivated for 7 days. Total RNA was isolated from the Sertoli cell culture (for AMH-Cre/WT 5 mice and WT/WT 3 mice) and the same genotypes were pooled together. For the microarray analysis two technical replicates for each genotype were generated.
2012-01-01 | E-GEOD-28307 | biostudies-arrayexpress
Project description:<p>Sertoli cell-only syndrome is severe form of human male infertility in which most seminiferous tubules appear to lack all spermatogenic cells, including spermatogonial stem cells (SSCs). However, a few small tubule segments of some patients have active spermatogenesis and, thus, functional stem cell niches and SSCs. Normally SSCs replicate, migrate and refill adjacent empty niches, but this does not appear to occur in SCO syndrome. We hypothesized that this failure occurs because most niches are dysfunctional. As Sertoli cells are essential to formation of these niches, we used RNAseq to compare the transcriptomes of human testes with qualitatively normal (complete) spermatogenesis (n=4) with the transcriptomes of human testes with SCO syndrome (n=7). We then focused our analysis on the expression of transcripts that bioinformatic analyses identified as Sertoli cell signature transcripts. Results show that Sertoli cells in SCO testes express abnormally low levels of GDNF, FGF8 and BMP4, all of which are important regulators of mouse SSCs and/or progenitor spermatogonia. Sertoli cells in SCO testes express significantly reduced levels of transcripts for proteins that polarize the Sertoli cell plasma membrane and regulate the trafficking of cell adhesion and gap junction proteins in and out of that plasma membrane.</p>
| phs001777 | dbGaP
Project description:Metastatic malignant melanoma is the deadliest skin cancer type, and it is characterized by its high resistance to apoptosis. The main driving mutations in melanoma cause hyperactivation of genes within the ERK pathway, with BRAF mutations being the most frequent ones, followed by NRAS, NF1 and MEK mutations. Increasing evidence shows that the MST2/Hippo pathway is also deregulated in this cancer type. While mutations are rare, MST2/Hippo pathway core proteins expression levels are often dysregulated in melanoma. The expression of the tumour suppressor RASSF1A, a bona fide activator of the pro-apoptotic MST2 pathway, is silenced by promoter methylation in over half of melanomas and correlates with poor prognosis. Here, using mass spectrometry-based interaction proteomics we identified Second Mitochondria-derived Activator of Caspases (SMAC) as a novel LATS1 interactor. We show that RASSF1A-dependent activation of the pro-apoptotic MST2 pathway promotes LATS1-SMAC interaction and negatively regulates the anti-apoptotic signal mediated by the members of the IAP family. Moreover, proteomic experiments identified a common cluster of the apoptotic regulator that bind to SMAC and LATS1. Mechanistic analysis show that the LATS1-SMAC complex promotes XIAP ubiquitination and its subsequent degradation which ultimately results apoptosis. Importantly, we show that the oncogenic BRAFV600E mutant prevents the pro-apoptotic signal mediated by the LAST1-SMAC complex while treatment of melanoma cell lines with BRAF inhibitors promotes this complex, indicating that inhibition of the LATS1-SMAC might be necessary for BRAFV600E-driven melanoma. Finally, we show that LATS1-SMAC interaction is regulated by the SMAC mimetic Birinapant which requires the inhibition of C-IAP1 and the degradation of XIAP, indicating that the MST2/Hippo pathway is part of the mechanism of action of Birinapant. Overall, the current work shows SMAC-dependent apoptosis is regulated by the LATS1 tumour suppressor and supports the idea that LATS1 is a signalling hub that regulates the crosstalk between the MST2 pathway, the apoptotic network and the RAF/ERK pathway.
2022-08-18 | PXD032781 | Pride
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