Differentiation of Embryonic Stem Cells 1 (Dies1) Is a Component of Bone Morphogenetic Protein 4 (BMP4) Signaling Pathway Required for Proper Differentiation of Mouse Embryonic Stem Cells

Aloia, Luigi; Parisi, Silvia; Fusco, Ludovico; Pastore, Lucio; Russo, Tommaso

doi:10.1074/jbc.m109.077156

Cited by 52 publications

(78 citation statements)

References 26 publications

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“…ESC differentiation into neuroectoderm was induced though SFEB formation. 2,20 SFEBs were induced by placing 1x10 6 ESCs in 100-mm Petri dishes in the following differentiation medium: GMEM supplemented with 2 mM glutamine, 1 mM sodium pyruvate, 1 × nonessential amino acids, 0.1 mM β-mercaptoethanol and 10% KSR.…”

Section: Methodsmentioning

confidence: 99%

“…After rehydration and permeabilization, the samples were treated as previously described. 20 Nuclei were counterstained with DAPI (Calbiochem, 1 : 1000) or, for confocal analysis, with DRQ5 (Cell Signaling, 1 : 1000) as indicated in the Figures. The following primary antibodies were used: anti-Oct3/4 (1 : 200), anti-Nanog (1 : 500; Calbiochem), antiSox1 (1 : 100) and anti-cleaved caspase 3 (1 : 300).…”

Section: Methodsmentioning

confidence: 99%

“…19 This regulation occurs through an efficient auto-regulatory loop in which BMP4 controls the transcription of miR-125a that targets the BMP4 co-receptor, Dies1. 20 As a consequence, this mechanism sets ESC sensitivity to BMP4. It is quite reasonable that the interplay between the BMP4 pathway and the transcription of miRNAs may represent a more general regulatory mechanism modulating the response of ESCs to extracellular stimuli.…”

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confidence: 99%

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miR-23a, miR-24 and miR-27a protect differentiating ESCs from BMP4-induced apoptosis

et al. 2014

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Numerous studies have indicated that BMP4 signaling is involved in the regulation of the early steps of development. In mouse embryonic stem cells (ESCs), BMP4 is crucial to sustain pluripotency and blocks differentiation towards neural fate. Here, through a systematic analysis of miRNAs in ESCs, we establish that BMP4 signaling regulates miR-23a, 27a and 24-2, through the recruitment of phospho-Smads at the promoter of the gene encoding this miRNA cluster. Suppression of miR-23a/b, 27a/b and 24 does not affect self-renewal or pluripotency, but induces an evident change of ESC differentiation, with a significant increase of the cells undergoing apoptosis after the transition from ESCs to epiblast stem cells (EpiSCs). BMP4 has been previously reported to cause apoptosis during ESC differentiation. By blocking BMP4 signaling, we completely prevent the apoptosis induced by suppression of the miRs. This suggests that the effects of miR suppression are the result of enhanced BMP4 signaling. This hypothesis is further supported by the observation that Smad5, the transcription factor downstream of the BMP4 receptor, is targeted by the miRNAs of the 23a and 23b clusters. Altogether, our results highlight the existence of a regulatory loop, involving Smad5 and the miR-23a clusters, that modulates the apoptotic response of ESCs to BMP4. Cell Death and Differentiation (2015) 22, 1047-1057 doi:10.1038/cdd.2014; published online 5 December 2014ESCs represent a precious experimental model of the early stages of embryo development. They can be grown indefinitely in vitro and induced to differentiate, thus mimicking two events taking place in the blastocyst: (i) the differentiation of the cells of the inner cell mass into epiblast cells and (ii) the commitment of epiblast cells to neuroectodermal or mesendodermal precursors. 1,2 These differentiation events are regulated by extrinsic signals. BMP4, a member of the TGF-β superfamily of cytokines, has a crucial role in ESCs. Many results indicate that it is able, together with LIF, to maintain mouse ESCs in the pluripotent state. 3 This effect is mediated by the regulation of many direct targets of Smad1, 5 and 8, the transcription factors downstream of the BMP4 receptor. 4 BMP4 also contributes to govern early steps of differentiation. First, BMP4 acts by regulating ESC-epiblast transition and then by suppressing neural differentiation and promoting non-neural lineage formation. 2 Moreover, BMP4 promotes the differentiation towards mesendodermal lineages and also regulates, either positively or negatively, the further commitment of mesendodermal precursors into their different fates. [5][6][7][8] Gene expression in ESCs is regulated by a complex network of transcription factors. 9,10 In addition, numerous results indicate that miRNAs are crucial regulators of the gene expression programs that drive ESC differentiation. Suppression of miRNA biogenesis, obtained by knocking out Dicer or DCGR8 genes, leads to an early arrest of mouse embryonic development and of in vitro differenti...

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Section: Methodsmentioning

confidence: 99%

Section: Methodsmentioning

confidence: 99%

mentioning

confidence: 99%

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miR-23a, miR-24 and miR-27a protect differentiating ESCs from BMP4-induced apoptosis

et al. 2014

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“…Here we describe a fast and simple method that we have been successfully used [15][16][17] to generate neurons and different neuronal-subtypes from mouse ESCs, in the absence of any specific inducing factors and without EB formation. Moreover, here we describe a modification of our differentiation method that turned out to be a useful tool to easily screen and identify molecules that increase neuronal differentiation of ESCs.…”

Section: Introductionmentioning

confidence: 99%

A Flexible Method to Study Neuronal Differentiation of Mouse Embryonic Stem Cells

et al. 2010

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Embryonic Stem Cells (ESCs) represent an invaluable tool for the study of early mammalian development, for regenerative medicine and for drug discovery. To fulfill these promises, efficient and easy protocols to differentiate ESCs have to be developed. Most of these protocols results in low efficiency of neural induction and/or requires extended in vitro culture. Here we describe in detail an easy and efficient method to differentiate ESCs into neurons, that can be used to identify molecules required for proper neuronal differentiation. Moreover, we present a modification of this method that allows to clearly evaluate the ability of some molecules to favor neuron formation in vitro. These methods can represent an efficient platform for studying the molecular mechanisms underlying early events of neural induction and differentiation in ESCs, as well as for testing molecule efficacy in the pharmaceutical testing.

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“…Human VISTA protein is expressed on CD4 + and CD8 + T cells, subsets of CD11b hi monocytes, lymphoid and myeloid dendritic cell subsets, and neutrophils (148). The cell surface receptor for VISTA is not yet known, but VISTA interacts with Alk3, a component of the BMP4 receptor complex, and controls BMP4 signaling in mouse embryonic stem cells (149). Recent work has demonstrated that homophilic interactions of VISTA contribute to myeloid cell phagocytosis of apoptotic cells (150).…”

Section: V-domain Immunoglobulin-containing Suppressor Of T Cell Actimentioning

confidence: 99%

Coinhibitory Pathways in Immunotherapy for Cancer

Baumeister

Freeman

Dranoff

et al. 2016

Annu. Rev. Immunol.

788

777

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The immune system is capable of recognizing tumors and eliminates many early malignant cells. However, tumors evolve to evade immune attack, and the tumor microenvironment is immunosuppressive. Immune responses are regulated by a number of immunological checkpoints that promote protective immunity and maintain tolerance. T cell coinhibitory pathways restrict the strength and duration of immune responses, thereby limiting immune-mediated tissue damage, controlling resolution of inflammation, and maintaining tolerance to prevent autoimmunity. Tumors exploit these coinhibitory pathways to evade immune eradication. Blockade of the PD-1 and CTLA-4 checkpoints is proving to be an effective and durable cancer immunotherapy in a subset of patients with a variety of tumor types, and additional combinations are further improving response rates. In this review we discuss the immunoregulatory functions of coinhibitory pathways and their translation to effective immunotherapies for cancer.

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Differentiation of Embryonic Stem Cells 1 (Dies1) Is a Component of Bone Morphogenetic Protein 4 (BMP4) Signaling Pathway Required for Proper Differentiation of Mouse Embryonic Stem Cells

Cited by 52 publications

References 26 publications

miR-23a, miR-24 and miR-27a protect differentiating ESCs from BMP4-induced apoptosis

miR-23a, miR-24 and miR-27a protect differentiating ESCs from BMP4-induced apoptosis

A Flexible Method to Study Neuronal Differentiation of Mouse Embryonic Stem Cells

Coinhibitory Pathways in Immunotherapy for Cancer

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