BMP-4 is required for hepatic specification of mouse embryonic stem cell–derived definitive endoderm

Gouon-Evans, Valérie; Boussemart, Lise; Gadue, Paul; Nierhoff, Dirk; Koehler, Christoph; Kubo, Atsushi; Shafritz, David A.; Keller, Gordon

doi:10.1038/nbt1258

Cited by 385 publications

(417 citation statements)

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“…Gouon-Evans et al [58] generated an endoderm progenitor population by culturing ES cells in the presence of activin in serum-free conditions, and specified these progenitors with BMP-4, activin, and fibroblast growth factor (FGF) in the development of hepatic populations highly enriched (45-70%) for cells expressing albumins. During embryogenesis, expression of Pdx1 (pancreatic and duodenal homeobox gene 1) marks the dorsal and ventral pancreatic buds, which generate all pancreatic lineages, i.e.…”

Section: Endoderm Derivativesmentioning

confidence: 99%

Roles of TGF-β family signaling in stem cell renewal and differentiation

2008

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Section: Endoderm Derivativesmentioning

confidence: 99%

Roles of TGF-β family signaling in stem cell renewal and differentiation

2008

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“…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.…”

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confidence: 99%

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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“…In mouse ES cell-based differentiation systems, Brachyury is widely used as a mesoendoderm marker, and Brachyury-positive cells were able to differentiate into mesodermal and definitive endodermal lineages, such as cardiomyocytes and hepatocytes (8)(9)(10). In a previous study, we found that depletion of a core promoter factor, the TATA binding protein-associated factor 3, in ES cells leads to significant up-regulation of Brachyury and mesoderm lineages during ES cell differentiation (11).…”

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Charting Brachyury-mediated developmental pathways during early mouse embryogenesis

Lolas

Valenzuela

Tjian

et al. 2014

Proc. Natl. Acad. Sci. U.S.A.

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To gain insights into coordinated lineage-specification and morphogenetic processes during early embryogenesis, here we report a systematic identification of transcriptional programs mediated by a key developmental regulator-Brachyury. High-resolution chromosomal localization mapping of Brachyury by ChIP sequencing and ChIP-exonuclease revealed distinct sequence signatures enriched in Brachyury-bound enhancers. A combination of genomewide in vitro and in vivo perturbation analysis and cross-species evolutionary comparison unveiled a detailed Brachyury-dependent gene-regulatory network that directly links the function of Brachyury to diverse developmental pathways and cellular housekeeping programs. We also show that Brachyury functions primarily as a transcriptional activator genome-wide and that an unexpected gene-regulatory feedback loop consisting of Brachyury, Foxa2, and Sox17 directs proper stem-cell lineage commitment during streak formation. Target gene and mRNA-sequencing correlation analysis of the T c mouse model supports a crucial role of Brachyury in up-regulating multiple key hematopoietic and musclefate regulators. Our results thus chart a comprehensive map of the Brachyury-mediated gene-regulatory network and how it influences in vivo developmental homeostasis and coordination.primitive streak | early development | mesoendoderm differentiation I n the past decade, significant insights have been gained in understanding gene-regulatory programs responsible for embryonic stem (ES) cell pluripotency and self-renewal. However, transcriptional control mechanisms underlying finely balanced lineage-segregation and morphogenetic processes during early mammalian embryogenesis remained elusive. During early mouse gastrulation, Brachyury (T), a classical enhancer-binding transcription factor (TF), has been reported to be required for the proper development of primitive streak, allantois, axial, and posterior mesoderm (reviewed in ref. 1).Specifically, mouse embryos that are homozygous for the Brachyury (T) deletion die at midgestation (2). T −/− mutant epiblast cells are compromised in their ability to migrate away from the primitive streak and, therefore, are unable to undergo the morphogenetic movements carried out by their wild-type (WT) counterparts during gastrulation. In addition to defects in the primitive streak, the notochord is absent in posterior portions of the embryo. Although the anterior portions of T mutant mice contain notochordal precursor-like cells, they fail to undergo normal terminal differentiation (3, 4). The embryonic pattern posterior to the forelimb region of T −/− animals is also disturbed, with somites posterior to the seventh pair absent or abnormal. Although neural folds fuse to form the neural tube, they are severely kinked in the caudal region, and the surface ectoderm tends to form fluid-filled blisters (2, 4, 5). In addition to these well-documented defects, numerous other phenotypic abnormalities have been reported in T −/− and T mutant embryos, including left-right pattern...

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BMP-4 is required for hepatic specification of mouse embryonic stem cell–derived definitive endoderm

Cited by 385 publications

References 44 publications

Roles of TGF-β family signaling in stem cell renewal and differentiation

Roles of TGF-β family signaling in stem cell renewal and differentiation

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

Charting Brachyury-mediated developmental pathways during early mouse embryogenesis

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