Myocyte Enhancer Factor 2C and Nkx2–5 Up-regulate Each Other's Expression and Initiate Cardiomyogenesis in P19 Cells

Skerjanc, Ilona S.; Petropoulos, Helen; Ridgeway, Alan G.; Wilton, Sharon

doi:10.1074/jbc.273.52.34904

Cited by 133 publications

(127 citation statements)

References 74 publications

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“…Overexpression of cardiac transcription factors can be used to direct differentiation of ES cells toward a cardiac lineage (Grepin et al, 1997;Skerjanc et al, 1998;David et al, 2008). This is likely due to an activation of a transcriptional regulatory network by the particular overexpressed factor.…”

Section: Discussionmentioning

confidence: 99%

Tbx5 overexpression favors a first heart field lineage in murine embryonic stem cells and in Xenopus laevis embryos

Herrmann

Bundschu

Kühl

et al. 2011

Developmental Dynamics

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The T-box transcription factor Tbx5 is involved in several developmental processes including cardiogenesis. Early steps of cardiac development are characterised by the formation of two cardiogenic lineages, the first (FHF) and the second heart field (SHF) lineage, which arise from a common cardiac progenitor cell population. To further investigate the function of Tbx5 during cardiogenesis, we generated a murine embryonic stem cell line constitutively overexpressing Tbx5. Differentiation of these cells is characterised by an earlier and increased appearance of contracting cardiomyocytes that beat with a higher frequency than control cells. In semi-quantitative and quantitative RT-PCR analyses, we observed an up-regulation of cardiac marker genes such as Troponin T, endogenous Tbx5, and Nkx2.5 and a down-regulation of others like BMP4 and Hand2. Similar data were gained in Xenopus laevis arguing for a conserved function of Tbx5. Furthermore, markers of the conduction system and atrial cardiomyocytes were increased.

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Section: Discussionmentioning

confidence: 99%

Tbx5 overexpression favors a first heart field lineage in murine embryonic stem cells and in Xenopus laevis embryos

Herrmann

Bundschu

Kühl

et al. 2011

Developmental Dynamics

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“…Several transcription factors having an essential role in cardiogenesis are up-regulated in DMSO-induced P19 cells. This was shown to be the case for the zinc-finger-containing GATA-4, the homeobox gene Nkx2-5, and the myocyte enhancer factor 2C (30,31,38), and the overexpression of either factor in P19 cells was sufficient to induce cardiac differentiation in the absence of DMSO (30,39,40). Little is known about the molecular mechanisms underlying the activation of these genes, but DMSO was found to increase intracellular Ca 2ϩ levels and was suspected to affect a pathway that has an extracellular component, possibly serum-borne (25,41,42).…”

Section: Discussionmentioning

confidence: 99%

Oxytocin induces differentiation of P19 embryonic stem cells to cardiomyocytes

Paquin

Danalache

Jankowski

et al. 2002

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

210

175

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We recently discovered the existence of the oxytocin͞oxytocin receptor (OT͞OTR) system in the heart. Activation of cardiac OTR stimulates the release of atrial natriuretic peptide (ANP), which is involved in regulation of blood pressure and cell growth. Having observed elevated OT levels in the fetal and newborn heart at a stage of intense cardiomyocyte hyperplasia, we hypothesized a role for OT in cardiomyocyte differentiation. We used mouse P19 embryonic stem cells to substantiate this potential role. P19 cells give rise to the formation of cell derivatives of all germ layers. Treatment of P19 cell aggregates with dimethyl sulfoxide (DMSO) induces differentiation to cardiomyocytes. In this work, P19 cells were allowed to aggregate from day 0 to day 4 in the presence of 0.5% DMSO, 10 ؊7 M OT and͞or 10 ؊7 M OT antagonist (OTA), and then cultured in the absence of these factors until day 14. OT alone stimulated the production of beating cell colonies in all 24 independently growing cultures by day 8 of the differentiation protocol, whereas the same result was obtained in cells induced by DMSO only after 12 days. Cells induced with OT exhibited increased ANP mRNA, had abundant mitochondria (i.e., they strongly absorbed rhodamine 123), and expressed sarcomeric myosin heavy chain and dihydropyridine receptor-␣1, confirming a cardiomyocyte phenotype. In addition, OT as well as DMSO increased OTR protein and OTR mRNA, and OTA completely inhibited the formation of cardiomyocytes in OT-and DMSO-supplemented cultures. These results suggest that the OT͞OTR system plays an important role in cardiogenesis by promoting cardiomyocyte differentiation.

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“…The expression of MEF2C before the expression of the MRF family members may indicate that MEF2C initiates the expression of the MRFs in P19 cells. However, an alternative explanation is that cardiac muscle precursor cells are formed under the serum conditions used and that the expression of MEF2C is the result of early stages of cardiomyogenesis (47,86). Due to the heterogeneity of the cultures after aggregation, distinguishing between the two possibilities is difficult.…”

Section: Expression Of Factors Involved In Somite Patterningmentioning

confidence: 97%