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Yap1-Scribble polarization is required for hematopoietic stem cell division and fate

ABSTRACT: Yap1 and its paralogue Taz largely control epithelial tissue growth. We have identified that hematopoietic stem cell (HSC) fitness response to stress depends on Yap1 and Taz. Deletion of Yap1 and Taz induces a loss of HSC quiescence, symmetric self-renewal ability and renders HSC more vulnerable to serial myeloablative 5-fluorouracil treatment. This effect depends on the predominant cytosolic polarization of Yap1 through its PDZ domain-mediated interaction with the scaffold Scribble. Scribble and Yap1 coordinate to control cytoplasmic Cdc42 activity and HSC fate determination in vivo. Deletion of Scribble disrupts Yap1 co-polarization with Cdc42 and decreases Cdc42 activity, resulting in increased selfrenewing HSC with competitive reconstitution advantages. These data suggest that Scribble/Yap1 co-polarization is indispensable for Cdc42- dependent activity on HSC asymmetric division and fate. The combined loss of Scribble, Yap1 and Taz results in transcriptional upregulation of Rac-specific guanine nucleotide exchange factors, Rac activation and HSC fitness restoration. Scribble links Cdc42 and the cytosolic functions of the Hippo signaling cascade in HSC fate determination.

ORGANISM(S): Mus musculus

PROVIDER: GSE151465 | GEO | 2020/05/30

REPOSITORIES: GEO

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CDC42 controlled apical-basal polarity regulates intestinal stem cell to transit amplifying cell fate transition via YAP-EGF-mTOR signaling

Project description:Epithelial polarity is controlled by a polarity machinery including the Rho GTPase CDC42 and Scribble/PAR. By using intestinal stem cell (ISC)-specific deletion of CDC42 in Olfm4-IRES-eGFPCreERT2;CDC42flox/flox mice, we found that ISC-initiated CDC42 loss caused a drastic hyper-proliferation of transit amplifying (TA) cells and disrupted epithelial polarity. CDC42-null crypts displayed expanded TA cell and diminished ISC populations, accompanied by elevated hippo signaling via YAP/TAZ - Ereg and mTOR activation, independent from canonical Wnt signaling. YAP/TAZ conditional knockout restored the balance of ISC/TA cell populations and crypt proliferation but did not rescue the polarity in CDC42-null small intestine. mTOR or EGFR inhibitor treatment of CDC42 KO mice exhibited similar rescuing effects without affecting YAP/TAZ signaling. Inducible ablation of Scribble in intestinal epithelial cells mimics that of CDC42 KO defects including crypt hyperplasia and hippo signaling activation. Mammalian epithelial polarity regulates ISC and TA cell fate and proliferation via a hippo-Ereg-mTOR cascade.

2021-10-23 | GSE166736 | GEO

Yap1-Scribble polarization is required for hematopoietic stem cell division and fate

Project description:Yap1-Scribble polarization is required for hematopoietic stem cell division and fate

| PRJNA635915 | ENA

Roles of Cdc42 and Rac in Bergmann glia during cerebellar corticogenesis (U87_CDC42RAC1-DKD)

Project description:Bergmann glia (BG) are important in the inward type of radial migration of cerebellar granule neurons (CGNs). However, details regarding the functions of Cdc42 and Rac in BG for radial migration of CGN are unknown. To examine the roles of Cdc42 and Rac in BG during cerebellar corticogenesis, mice with a single deletion of Cdc42 or Rac1 and those with double deletions of Cdc42 and Rac1 under control of the glial fibrillary acidic protein (GFAP) promoter: GFAP-Cre;Cdc42flox/flox (Cdc42-KO), GFAP–Cre;Rac1flox/flox (Rac1-KO), and GFAP-Cre;Cdc42 flox/flox;Rac1flox/flox (Cdc42/Rac1-DKO) mice, were generated. Both Cdc42-KO and Rac1-KO mice, but more obviously Cdc42-KO mice, had disturbed alignment of BG in the Purkinje cell layer (PCL). We found that Cdc42-KO, but not Rac1-KO, induced impaired radial migration of CGNs in the late phase of radial migration, leading to retention of CGNs in the inferior half of the molecular layer (ML). Cdc42-KO, but not Rac1-KO, mice also showed aberrantly aligned Purkinje cells (PCs). These phenotypes were exacerbated in Cdc42/Rac1-DKO mice. Alignment of BG radial fibers in the ML and BG endfeet at the pial surface of the cerebellum evaluated by GFAP staining was disturbed and weak in Cdc42/Rac1-DKO mice, respectively. Our data indicate that that Cdc42 and Rac, but predominantly Cdc42, in BG play important roles during the late phase of radial migration of CGNs. We also report here that Cdc42 is involved in gliophilic migration of CGNs, in contrast to Rac, which is more closely connected to regulating neurophilic migration.

2018-01-01 | GSE106142 | GEO

Roles of Cdc42 and Rac in Bergmann glia during cerebellar corticogenesis (WT_primary_astrocyte)

2018-01-01 | GSE106141 | GEO

YAP/TAZ drives ependymoma-like tumour formation in mice

Project description:YAP1 gene fusions have been observed in a subset of paediatric ependymomas. Here we show that, ectopic expression of active nuclear YAP1 (nlsYAP5SA) in ventricular zone neural progenitor cells using conditionally-induced NEX/NeuroD6-Cre is sufficient to drive brain tumour formation in mice. Neuronal differentiation is inhibited in the hippocampus. Deletion of YAP1’s negative regulators LATS1 and LATS2 kinases in NEX-Cre lineage in double conditional knockout mice also generates similar tumours, which are rescued by deletion of YAP1 and its paralog TAZ. YAP1/TAZ-induced mouse tumours display molecular and ultrastructural characteristics of human ependymoma. RNA sequencing and quantitative proteomics of mouse tumours demonstrate similarities to YAP1-fusion induced supratentorial ependymoma. Finally, we find that transcriptional cofactor HOPX is upregulated in mouse models and in human YAP1-fusion induced ependymoma, supporting their similarity. Our results show that uncontrolled YAP1/TAZ activity in neuronal precursor cells leads to ependymoma-like tumours in mice.

2020-05-26 | PXD018131 | Pride

Effect of YAP1/TAZ on rumen epithelial cell proliferation

Project description:Promoting rumen development is closely related to the health and efficient growth of ruminants. In the present study, we aimed to assess the impact of YAP1/TAZ on RE proliferation. The transcriptomic expression was analyzed to investigate the potential regulatory networks. The results indicated that GA promoted RE cell proliferation, while VP disrupted RE cell proliferation. The Hippo, Wnt, and calcium signaling pathways were altered in cells following the regulation of YAP1/TAZ. Upon YAP1/TAZ activation through GA, the CCN1/2 increased to promote RE cell proliferation. While when the YAP1/TAZ was inhibited by VP, the BIRC3 decreased to suppress RE cell proliferation. Thus, YAP1/TAZ may be potential targets for regulating RE cell proliferation. These findings broaden our understanding of the role of YAP1/TAZ and their regulators in RE and offer a potential target for promoting rumen development.

2024-04-03 | GSE252747 | GEO

RNA-Sequencing analysis of liver tissue from female Foxa3-Cre YAP1 knockout mice, Foxa3-Cre YAP1 KO TAZ heterozygous mice, and WT littermate controls, at 3-4 months of age

Project description:We developed a mouse model of bile duct paucity by deleting Yes-associated protein 1 (YAP1) in foregut endoderm progenitors, using the Foxa3 promoter to drive Cre expression. YAP1 KO mice are viable postnatally and survive long-term despite a complete failure of intrahepatic bile duct development, resembling the liver phenotype of Alagille syndrome. Adult YAP1 KO mice suffer from severe chronic cholestasis, but show minimal hepatocellular injury, suggesting that the hepatocytes have adapted to preserve liver function and reduce damage from the toxicity of bile acids and bilirubin. We next bred Foxa3-Cre YAP1 KO TAZ heterozygote and Foxa3-Cre YAP1 KO TAZ KO (DKO) mice to assess the role of TAZ in this model. DKO mice and male YAP KO TAZ heterozygotes died around time of birth. The survivors, YAP1 KO TAZ heterozygote females, were overall phenotypically similar to YAP1 KO mice, with absence of intrahepatic bile ducts and long-term survival. We used RNA-seq to analyze the gene expression patterns of whole liver tissue of female adult YAP1 KO mice compared to WT controls (C57BL/6 background), and female adult YAP1 KO TAZ heterozygote (YKTH) mice compared to WT controls (mixed C57BL/6 - FVB background). We found that both YAP1 KO and YAP1 KO TAZ heterozygote female mice were overall very similar and showed similar alterations in gene expression compared to WT. There were a few differences in pathways involved in cell cycling and monocyte recruitment.

2023-07-20 | GSE213815 | GEO

Effect of sodium butyrate on rumen epithelial cell proliferation

Project description:Promoting rumen development is closely related to the health and efficient growth of ruminants. We investigated the effect of sodium butyrate (SB) on rumen epithelium (RE), and whether the YAP1/TAZ-dependent alteration was involved in the RE developmental process induced by sodium butyrate. In the SB-treated cells, theYAP1/TAZ-dependent changes were not observed. SB increased the expression of genes involved in short-chain fatty acid (SCFA) metabolism, while YAP1/TAZ did not. Thus, SB mediated RE development was not associated with YAP1/TAZ.

2024-04-03 | GSE252749 | GEO

Cell fate determinant Llgl1 is required for propagation of acute myeloid leukemia

Project description:Scribble complex proteins can influence cell fate decisions and self-renewal capacity of hematopoietic cells. While specific cellular functions of Scribble complex members appear to be conserved in mammalian hematopoiesis, they appear to be highly context dependent. Using CRISPR/Cas9-based genetic screening, we have identified Scribble complex-related liabilities in AML including LLGL1. Despite its reported suppressive function in HSC self-renewal, inactivation of LLGL1 in AML confirms its relevant role for proliferative capacity and development of AML. Its function was conserved in human and murine models of AML and across various genetic backgrounds. Loss of LLGL1 results in loss of stemness-associated gene-expression including HoxA-genes and induces a GMP-like phenotype in leukemic cells. Finally, re-expression of HoxA9 facilitates functional and phenotypic rescue. Collectively, these data establish LLGL1 as a specific dependency and putative target in AML and emphasizes its cell-type specific functions.

2023-08-03 | GSE233381 | GEO

YAP/TAZ drives ependymoma-like tumour formation in mice

Project description:YAP1 gene fusions have been observed in a subset of paediatric ependymomas. Here we show that ectopic expression of active nuclear YAP1 (nlsYAP5SA) in ventricular zone neural progenitor cells using conditionally-induced NEX/NeuroD6-Cre is sufficient to drive brain tumour formation in mice. Neuronal differentiation is inhibited in the hippocampus. Deletion of YAP1’s negative regulators LATS1 and LATS2 kinases in NEX-Cre lineage in double conditional knockout mice also generates similar tumours, which are rescued by deletion of YAP1 and its paralog TAZ. YAP1/TAZ-induced mouse tumours display molecular and ultrastructural characteristics of human ependymoma. RNA sequencing and quantitative proteomics of mouse tumours demonstrate similarities to YAP1-fusion induced supratentorial ependymoma. Finally, we find that transcriptional cofactor HOPX is upregulated in mouse models and in human YAP1-fusion induced ependymoma, supporting their similarity. Our results show that uncontrolled YAP1/TAZ activity in neuronal precursor cells leads to ependymoma-like tumours in mice.

2020-04-16 | GSE147961 | GEO

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