The p38MAPK pathway

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Among the four p38MAPK isoforms, a, b, g, and d, only the knock-out of p38a  is embryonic lethal [38], the others presenting no apparent phenotype. The lethality is due to both embryonic defect and a lack of erythropoietin expression. It has been shown that the p38MAPK pathway plays a crucial role during early mammalian somite development and myotome formation, at E9.5 of the embryo development, by signaling to the MEF2 transcriptional regulators [39]. The p38a isoform is the only one expressed in ES cells [40]. Whereas no role has been assigned to p38MAPK in undifferentiated ES cells, p38MAPK activation is involved in the early apoptosis observed in a fraction of ES cells early on upon induction of differentiation [41]. Although p38MAPK protein expression is constant, two waves of p38MAPK activity characterise the ES cell differentiation process, one between day 2 to 5 [11, 41] and one, latter on, between day 12 to 16 [42]. By analysing both the effects of p38MAPK-specific pharmaceutical inhibitors and the in vitro differentiation capacities of ES cells deficient for the p38a gene, our laboratory found that these activities regulate ES cell commitment. The early peak of P38MAPK activity controls a switch between cardiomyogenesis (p38MAPK activity turned on) and neurogenesis (p38MAPK off) [11], while the second one inhibits adipogenesis [42].

Interestingly, RA treatment inhibited both the first peak of p38MAPK activation and the in vitro formation of cardiomyocytes. Therefore, it is likely that RA blocks cardiomyogenesis in ES cells via p38MAPK inhibition. Few studies have shown that RA modulates MAPK activity, however, a recent report demonstrated that RA inhibits cyclic stretch induced activity in neonatal cardiomyocytes via MAPK inhibition [43]. This inhibition could be due to an increase of expression of the MAPK phosphatases MKP-1 and -2 by RA. Either deletion of p38MAPK or specific inhibition of its peak of activity partially mimicked the in vitro RA inhibition of cardiomyogenesis and reduced expression of cardiomyocyte markers, including the important transcription factorMEF2C [11], which acts on many genes encoding cardiac structural proteins. Interestingly, p38MAPK is a well-known regulator of MEF2C [44-47]well known to be regulated by p38 , suggesting that the p38MAPK effect could be directly due to MEF2C regulation. Consistent with this hypothesis, a role for p38a in various aspects of cardiomyogenesis including the regulation of cardiomyocyte differentiation, apoptosis, and hypertrophy has been described [48-50], and, accordingly, p38a^-/- embryos present a massive reduction of the myocardiac muscle attributed to a defect in placental development [51].

In PC12 and P19 cell lines, p38MAPK activation is required for neurite formation and neuron survival during late stages of differentiation [52, 53]. In fact, the role of p38MAPK in these cells is restricted to the late stages of differentiation. Indeed, PC12 cells are already committed into the neuronal lineage [54] and P19 is a multipotent embryonic cell line [55, 56] that terminally differentiates into neurons after RA treatment. By contrast, analysis of the role of p38MAPK in the early stages of neuron differentiation, during ES cells commitment, revealed an opposite function for this kinase. Inhibition of p38MAPK using specific inhibitors or p38a^-/- cells is sufficient to induce, spontaneously, a high level of neurogenesis [11].

Altogether these results suggest that p38MAPK may exert different roles depending on the stage of neuronal differentiation: inhibitory during cell commitment and anti-apoptotic during the late stages of differentiation. It is very likely that the molecular mechanisms underlying these distinct functions are different and their identification should be of a great interest for the development of ES cells in therapeutic applications.