BMP-4 inhibits neural differentiation of murine embryonic stem cells

Finley, Michael; Devata, Sandeep; Huettner, James E.

doi:10.1002/(sici)1097-4695(19990905)40:3<271::aid-neu1>3.0.co;2-c

Cited by 101 publications

(56 citation statements)

References 61 publications

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“…The opposite effect was seen in cultures treated with the BMP inhibitor Noggin (Figure 4B). Similar to the time window that we identified as critical for CaN activity (Figure 2), the effectiveness of BMP treatment in altering cell fate during mESC differentiation has been reported to be limited to a period prior to the onset of neural differentiation (Finley et al, 1999). In the early mouse embryo Flk1(Kdr), which at later stages is a well-known marker for cardiovascular and hematopoietic progenitors, is highly expressed in multipotent mesodermal progenitors that exit from the posterior primitive streak (Ema et al, 2006).…”

Section: Resultssupporting

confidence: 68%

Calcineurin Signaling Regulates Neural Induction through Antagonizing the BMP Pathway

Cho

Tang

Davila

et al. 2014

Neuron

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Summary Development of the nervous system begins with neural induction, which is controlled by complex signaling networks functioning in concert with one another. Fine-tuning of the bone morphogenetic protein (BMP) pathway is essential for neural induction in the developing embryo. However, the molecular mechanisms by which cells integrate the signaling pathways that contribute to neural induction have remained unclear. We find that neural induction is dependent on the Ca2+-activated phosphatase calcineurin (CaN). FGF-regulated Ca2+ entry activates CaN, which directly and specifically dephosphorylates BMP-regulated Smad1/5 proteins. Genetic and biochemical analyses revealed that CaN adjusts the strength and transcriptional output of BMP signaling and that a reduction of CaN activity leads to an increase of Smad1/5-regulated transcription. As a result, FGF-activated CaN signaling opposes BMP signaling during gastrulation, thereby promoting neural induction and the development of anterior structures.

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Section: Resultssupporting

confidence: 68%

Calcineurin Signaling Regulates Neural Induction through Antagonizing the BMP Pathway

Cho

Tang

Davila

et al. 2014

Neuron

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“…Our observations reveal the importance of the state of the cell when responding to signals, particularly to those that promote both self-renewal and differentiation, like Wnt and BMP. Both signals have been suggested to suppress neural differentiation (Finley et al, 1999; Aubert et al, 2002; Watanabe et al, 2005; Watanabe and Sasai, 2005; Smith et al, 2008; Zhang et al, 2010; Surmacz et al, 2012; Bertacchi et al, 2013; Lupo et al, 2013); however, we find that at the exit from pluripotency, their effects on differentiation are mediated, mostly, through their effects on pluripotency. Our results support the conclusions that BMP delays the exit from pluripotency (Zhang et al, 2010; Malaguti et al, 2013) whilst simultaneously priming the PS state (Hansson et al, 2009; Engberg et al, 2010; Malaguti et al, 2013).…”

Section: Discussioncontrasting

confidence: 65%

“…To test if there was a similar change in the competence for NECT over the first two days of induced differentiation, we made use of the ability of BMP signalling to inhibit this event (Finley et al, 1999; Di-Gregorio et al, 2007; Zhang et al, 2010; Surmacz et al, 2012; Bertacchi et al, 2013). Treatment of ES cells with 1 ng/ml BMP4 for different periods of time (Fig.…”

Section: Resultsmentioning

confidence: 99%

An interplay between extracellular signalling and the dynamics of the exit from pluripotency drives cell fate decisions in mouse ES cells

et al. 2014

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Embryonic Stem cells derived from the epiblast tissue of the mammalian blastocyst retain the capability to differentiate into any adult cell type and are able to self-renew indefinitely under appropriate culture conditions. Despite the large amount of knowledge that we have accumulated to date about the regulation and control of self-renewal, efficient directed differentiation into specific tissues remains elusive. In this work, we have analysed in a systematic manner the interaction between the dynamics of loss of pluripotency and Activin/Nodal, BMP4 and Wnt signalling in fate assignment during the early stages of differentiation of mouse ES cells in culture. During the initial period of differentiation, cells exit from pluripotency and enter an Epi-like state. Following this transient stage, and under the influence of Activin/Nodal and BMP signalling, cells face a fate choice between differentiating into neuroectoderm and contributing to Primitive Streak fates. We find that Wnt signalling does not suppress neural development as previously thought and that it aids both fates in a context dependent manner. Our results suggest that as cells exit pluripotency they are endowed with a primary neuroectodermal fate and that the potency to become endomesodermal rises with time. We suggest that this situation translates into a “race for fates” in which the neuroectodermal fate has an advantage.

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“…BMP4 (Bone Morphogenetic Protein 4) is known to induce Tbx6 expression in P19 cells to inhibit neural differentiation (Finley et al, 1999). Thus, a mechanism of Tbx6 regulation during cardiac myocyte differentiation might also involve signaling through BMPs.…”

Section: Discussionmentioning

confidence: 99%

Tbx6 is a determinant of cardiac and neural cell fate decisions in multipotent P19CL6 cells

Gavrilov¹,

Nührenberg²,

Ashton³

et al. 2012

Differentiation

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Multipotent P19CL6 cells differentiate into cardiac myocytes or neural lineages when stimulated with dimethyl sulfoxide (DMSO) or retinoic acid (RA), respectively. Expression of the transcription factor Tbx6 was found to increase during cardiac myocyte differentiation and to decrease during neural differentiation. Overexpression of Tbx6 was not sufficient to drive P19CL6 cells to a cardiac myocyte fate or to accelerate DMSO-induced differentiation. In contrast, knockdown of Tbx6 dramatically inhibited DMSO-induced differentiation of P19CL6 cells to cardiac myocytes, as evidenced by the loss of striated muscle-specific markers and spontaneous beating. Tbx6 knockdown was also accompanied by almost complete loss of Nkx2.5, a transcription factor involved in the specification of the cardiac myocyte lineage, indicating that Nkx2.5 is downstream of Tbx6. In distinction to its positive role in cardiac myocyte differentiation, Tbx6 knockdown augmented RA-induced differentiation of P19CL6 cells to both neurons and glia, and accelerated the rate of neurite formation. Conversely, Tbx6 overexpression attenuated differentiation to neural lineages. Thus, in the P19CL6 model, Tbx6 is required for cardiac myocyte differentiation and represses neural differentiation. We propose a model in which Tbx6 is a part of a molecular switch that modulates divergent differentiation programs within a single progenitor cell.

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BMP-4 inhibits neural differentiation of murine embryonic stem cells

Cited by 101 publications

References 61 publications

Calcineurin Signaling Regulates Neural Induction through Antagonizing the BMP Pathway

Calcineurin Signaling Regulates Neural Induction through Antagonizing the BMP Pathway

An interplay between extracellular signalling and the dynamics of the exit from pluripotency drives cell fate decisions in mouse ES cells

Tbx6 is a determinant of cardiac and neural cell fate decisions in multipotent P19CL6 cells

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