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Arp2/3 complex activity is necessary for mouse ESC differentiation, times formative pluripotency, and enables lineage specification

ABSTRACT: Mouse embryonic stem cells (mESCs), a model for differentiation into primed epiblast-like cells (EpiLCs), have revealed transcriptional and epigenetic control of early embryonic development. The control and significance of morphological changes, however, remain less defined. We show marked changes in morphology and actin architectures during differentiation that depend on Arp2/3 complex but not formin activity. Inhibiting Arp2/3 complex activity pharmacologically or genetically does not block exit from naive pluripotency but attenuates increases in EpiLC markers. We find that inhibiting Arp2/3 complex activity delays formative pluripotency and causes globally defective lineage specification as indicated by RNA-sequencing, with significant effects on TBX3-depedendent transcriptional programs. We also identify two previously unreported indicators of mESC differentiation; MRTF and FHL2, which have inverse Arp2/3 complex-dependent nuclear translocation. Our findings on Arp2/3 complex activity in differentiation and the established role of formins in EMT indicate that these two actin nucleators regulate distinct modes of epithelial plasticity

ORGANISM(S): Mus musculus

PROVIDER: GSE175391 | GEO | 2022/04/01

REPOSITORIES: GEO

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Arp2/3 Complex Activity Enables Nuclear YAP for Naïve Pluripotency of Human Embryonic Stem Cells

Project description:Our understanding of transitions of human embryonic stem cells between distinct stages of pluripotency relies predominantly on regulation by transcriptional and epigenetic programs with limited insight on the role of established morphological changes. We report remodeling of the actin cytoskeleton of human embryonic stem cells (hESCs) as they transition from primed to naïve pluripotency that includes assembly of a ring of contractile actin filaments encapsulating colonies of naïve hESCs. Activity of the Arp2/3 complex is required for the actin ring, uniform cell mechanics within naïve colonies, nuclear translocation of the Hippo pathway effectors YAP and TAZ, and effective transition to naïve pluripotency. RNA-sequencing analysis confirms that Arp2/3 complex activity regulates Hippo signaling in hESCs, and impaired naïve pluripotency with inhibited Arp2/3 complex activity is rescued by expressing a constitutively active, nuclear-localized YAP-S127A. Moreover, expression of YAP-S127A partially restored in actin filament fence with Arp2/3 complex inhibition, suggesting that actin filament remodeling is both upstream and downstream of YAP activity. These new findings on the cell biology of hESCs reveal a mechanism for cytoskeletal dynamics coordinating cell mechanics to regulate gene expression and facilitate transitions between pluripotency states.

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Knockout of the Arp2/3 complex in epidermis causes a psoriasis-like disease hallmarked by hyperactivation of transcription factor Nrf2 [Epidermis ssRNA-Seq]

Project description:Arp2/3 complex assembles branched actin filaments key to many cellular processes, but its organismal roles remain poorly understood. Here we employed conditional arpc4 knockout mice to study the function of the Arp2/3 complex in the epidermis.We found that depletion of the Arp2/3 complex by knockout of arpc4 results in skin abnormalities at birth that evolve into a severe psoriasis-like disease hallmarked by hyperactivation of transcription factor Nrf2. Knockout of arpc4 in cultured keratinocytes was sufficient to induce nuclear accumulation of Nrf2, upregulation of Nrf2-target genes and decreased filamentous actin levels. Furthermore, pharmacological inhibition of the Arp2/3 complex unmasked the role of branched actin filaments in Nrf2 regulation. Consistently, we unveiled that Nrf2 associates with the actin cytoskeleton in cells and binds to filamentous actin in vitro Finally, we discovered that Arpc4 is downregulated in both human and mouse psoriatic epidermis. Thus, the Arp2/3 complex affects keratinocytes' shape and transcriptome through an actin-based cell-autonomous mechanism that influences epidermal morphogenesis and homeostasis.

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Knockout of the Arp2/3 complex in epidermis causes a psoriasis-like disease hallmarked by hyperactivation of transcription factor Nrf2 [Keratinocytes ssRNA-Seq]

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Arp2/3 complex mutants show a pronounced lack of hyphal specific gene expression in Candida albicans

Project description:Candida albicans is a diploid fungal pathogen lacking a defined complete sexual cycle, and thus has been refractory to standard forward genetic analysis. Instead, transcription profiling and reverse genetic strategies based on Saccharomyces cerevisiae have typically been used to link genes to functions. To overcome restrictions inherent in such indirect approaches, we have investigated a forward genetic mutagenesis strategy based on the UAU1 technology. We screened 4700 random insertion mutants for defects in hyphal development, and linked two new genes (ARP2 and VPS52) to hyphal growth. Deleting ARP2 abolished hyphal formation, generated round and swollen yeast phase cells, disrupted cortical actin patches and blocked virulence in mice. The mutants also showed a global lack of induction of hyphae-specific genes upon the yeast-to-hyphae switch. Surprisingly, both arp2Î/Î and arp2Î/Îarp3Î/Î mutants were still able to endocytose FM4-64 and Lucifer Yellow, although as shown by time-lapse movies internalization of FM4-64 was somewhat delayed in mutant cells. Thus the non-essential role of the Arp2/3 complex discovered by forward genetic screening in C. albicans showed that uptake of membrane components from the plasma membrane to vacuolar structures is not dependent on this actin nucleating machinery. By forward genetic screening, we have identified genes that are essential for hyphal formation. One of the hits is the Arp2/3 complex, which is essential for hyphal formation, but not for viability in Candida albicans. To gain insights into cellular processes affected by disrupting Arp2/3 complex functions, we performed transcriptional profiling under yeast growth conditions (YPD at 30Â°C for three hours) or hyphal induction (YPD + 10% FBS at 37Â°C for three hours) and compared transcriptional consequences of deleting ARP2 to MYO5 and SLA2 microarray data sets (Oberholzer et al., 2006).

2010-10-08 | E-GEOD-19565 | biostudies-arrayexpress

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Project description:Oncogenic KrasG12D, a driver mutation of pancreatic ductal adenocarcinoma (PDAC), induces neoplastic transformation of acinar cells through acinar-to-ductal metaplasia (ADM). Here, we show that both functional complexes of mTOR (mechanistic target of rapamycin kinase, mTORC1 and mTORC2) are specifically activated in ADM. Murine models uncover that mTORC1 and mTORC2 cooperate to promote KrasG12D-driven ADM development. Proteomic analyses identify Arp2/3 complex, an actin nucleator, as the common downstream effector: mTORC1 is responsible for the protein synthesis of Rac1 and Arp3 while mTORC2 promotes the Arp2/3 complex activity via Akt/Rac1 signalling. Genetic ablation of Arp2/3 complex completely arrests KrasG12D-driven ADM development. The Arp2/3 complex-mediated y-branching of actin network promotes the basolateral spread of filamentous actin, which is indispensable for acinar cells-initiated carcinogenesis. Induced by oncogenic KrasG12D, ADM is a metaplastic phenotype of acinar cells that requires extensive actin rearrangements. mTORC1 and mTORC2, downstream targets of KrasG12D, have well-established oncogenic functions in PDAC development. The actin-related protein 2/3 (Arp2/3) complex is the first identified actin nucleator. Regarded as textbook knowledge, it is activated by EGFR/Rac1 signalling to promote the polymerisation of branched actin filaments from pre-existing filaments in numerous biological contexts. Hereby, we identify that mTORC1 and mTORC2 attain a dual, yet non-redundant, regulatory role in promoting Arp2/3 complex function, which is responsible for generating basolateral filamentous actin in ADM. Thus, the role of Arp2/3 complex fills up the missing gap between putative oncogenic signals and actin dynamics underlying PDAC initiation.

2021-01-07 | PXD018296 | Pride

Arp2/3 complex activity is necessary for mouse ESC differentiation, times formative pluripotency, and enables lineage specification

Project description:Arp2/3 complex activity is necessary for mouse ESC differentiation, times formative pluripotency, and enables lineage specification

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Arp2/3 Complex Activity Enables Nuclear YAP for Naïve Pluripotency of Human Embryonic Stem Cells

Project description:Arp2/3 Complex Activity Enables Nuclear YAP for Naïve Pluripotency of Human Embryonic Stem Cells

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Arp2/3 complex mutants show a pronounced lack of hyphal specific gene expression in Candida albicans

2010-01-23 | GSE19565 | GEO

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Forward genetics in Candida albicans reveals the Arp2/3 complex is required for hyphal formation, but not endocytosis

Project description:This SuperSeries is composed of the following subset Series: GSE19565: Arp2/3 complex mutants show a pronounced lack of hyphal specific gene expression in Candida albicans GSE19582: Partial de-repression of the hyphal program does not restore hyphae formation in absence of a functional Arp2/3 complex Refer to individual Series

2010-05-15 | E-GEOD-19583 | biostudies-arrayexpress

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