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作者：Bernard Bintruya,b, Lynn Heasleyc, Frdric Bostd,e, Leslie Carond,e, Myriam Aouadid,e h7 l5 ~: g( X) W+ g
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【摘要】1 u& r% f! `, {/ ~; h, g
Embryonic stem (ES) cells can give rise, in vivo, to the ectodermal, endodermal, and mesodermal germ layers and, in vitro, can differentiate into multiple cell lineages, offering broad perspectives in regenerative medicine. Understanding the molecular mechanisms governing ES cell commitment is an essential challenge in this field. The mitogen-activated protein kinase (MAPK) pathways extracellular signal-regulated kinase (ERK), c-Jun amino-terminal kinase (JNK), and p38MAPK are able to regulate ES commitment from early steps of the process to mature differentiated cells. Whereas the ERK pathway inhibits the self-renewal of ES cells, upon commitment this pathway is involved in the development of extraembryonic tissues, in early mesoderm differentiation, and in the formation of mature adipocytes; p38MAPK displays a large spectrum of action from neurons to adipocytes, and JNK is involved in both ectoderm and primitive endoderm differentiations. Furthermore, for a given pathway, several of these effects are isoform-dependent, revealing the complexity of the cellular response to activation of MAPK pathways. Regarding tissue regeneration, the potential outcome of systematic analysis of the function of different MAPKs in different ES cell differentiation programs is discussed.$ X" ?2 I, _9 E j0 L7 B: _
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Disclosure of potential conflicts of interest is found at the end of this article.
! A& k$ x5 \. R$ c0 v- Z" l 【关键词】 Mitogen-activated protein kinases Embryonic stem cells commitment c-Jun amino-terminal kinase pathway pMAPK pathway Extracellular signal-regulated kinase pathway
. z. a, z; O" V0 r8 i INTRODUCTION
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Embryonic stem (ES) cells can give rise, in vivo, to the ectodermal, endodermal, and mesodermal germ layers and, in vitro, can differentiate into multiple cell lineages, offering broad perspectives in regenerative medicine (see for extensive reviews on mouse and human ES cells ). One existing limitation to the therapeutical use of these cells is that, in vitro, the capacity to orientate ES cells in a given lineage is often limited to a small proportion of cells. In fact, the cellular population obtained is usually a mixture of different specialized cells. Thus, understanding the molecular mechanisms governing the commitment of ES cells to specific lineages is an essential challenge in this field.( K5 R4 g9 k; [1 ]% O5 f
; t2 Z3 I _4 l7 M: O6 hMouse ES cells can be maintained, in vitro, in an undifferentiated state in the presence of a cytokine, the leukemia inhibitory factor (LIF) . It is almost certain that different differentiation protocols and inducers will selectively activate distinct signaling pathways that activate cell lineage-specific genetic programs to bring about the observed enrichment in differentiated cell populations. Yet, the precise molecular identity of these signaling pathways controlling cell differentiation of ES cells remains poorly understood. The purpose of this article is to review the recent studies that identify the role of mitogen-activated protein kinases (MAPKs) in the in vitro differentiation of ES cells.
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. N" r) F% o% o8 e) F# a) vTHE MITOGEN-ACTIVATED PROTEIN KINASE SIGNAL TRANSDUCTION PATHWAYS
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- @7 c+ I. H, A4 E9 D: a4 ACells respond to extracellular signals by engaging a variety of intracellular signaling pathways, which trigger both immediate and long-term cell responses. The latter activate cascades that signal to the nucleus and regulate gene expression. The signaling pathways leading to activation of MAPKs and their downstream effects on gene regulation represent a paradigm in cellular signaling (see reviews ). The MAPK family comprises four groups of proteins: extracellular signal-regulated kinases (ERKs) 1 and 2; ERK5; c-Jun amino-terminal kinases (JNKs) 1, 2, and 3; and p38MAPK , ¦Â, , and , where each isoform is encoded by its own gene. Much of the present understandings of the MAPKs, especially regarding ES cell signaling, arise from the study of ERK1/2, JNK, and p38MAPK proteins. These protein serine/threonine kinases are regulated by phosphorylation cascades organized in specific modules comprised of two additional protein kinases activated in series and leading to activation of a specific mitogen-activated protein (MAP) kinase: a MAP kinase kinase (MAPKK), which phosphorylates a specific MAPK, and a MAP kinase kinase kinase (MAPKKK), which phosphorylates a specific MAPKK (Fig. 1). Besides the activities of the different components of the cascades themselves, there are two other important means to specifically regulate these signaling pathways: interfering with the scaffolding proteins or MAPK phosphatases that are specific for each pathway.# o% b/ b& _! D
& V# f4 r7 q, {- a& LFigure 1. Schematic representation of the main mitogen-activated protein kinase signal transduction pathways and their regulators. Abbreviations: ERK, extracellular signal-regulated kinase; JNK, c-Jun amino-terminal kinase; K, kinase; MAPK, mitogen-activated protein kinase; MEK, MAP/ERK kinase; MKK, MAP kinase kinase.0 A/ e$ e* ^: d- r- w$ ~% ~
h) V/ [" B; H9 ^7 |8 X4 j) qTaking advantage of the development of specific chemical inhibitors for each MAPK pathway, numerous investigations have explored their biological functions and demonstrated their involvement in a wide variety of cellular functions. These multiple functions are dependent on the pathway that is activated and on the cellular model analyzed. In addition, the duration of the stimulus can also affect the cellular response. A wide panel of different stimuli are able to activate the MAPK pathways, but a good correlation has been found between the types of stimulus and the function assigned to the pathway. Schematically, ERK is preferentially activated by mitogens such as the serum or growth factors and, accordingly, this pathway is an important regulator of cell cycle and cell proliferation, whereas p38MAPK and JNK are responsive to various stress stimuli from UV to cytokines and constitute important mediators of cellular responses to these stimuli (see for extensive reviews ). For example, the JNK pathway is the mediator of apoptosis induced by tumor necrosis factor-. However, this growth factor is also able to activate the nuclear factor B pathway, which, in turn, inhibits JNK. Therefore, the cellular response will result from the combinatorial action of distinct signaling pathways.' S6 P( G9 T0 @- M- e, a4 A
/ y$ T3 Q3 b0 E% m4 h% ARegarding the process of differentiation, the role of MAPKs is extremely complex and depends on multiple parameters. The complexity is due, first, to the biological process itself, which, in general, involves distinct, successive steps. Furthermore, each of these steps can be modulated by MAPKs leading, sometimes, to opposite effects. Probably because of this complexity, most of the tools used for these studies have found their limitations. With regard to small molecule inhibitors of protein kinases, inhibitors of a given pathway differ widely in their inhibitory potency and specificity . Whereas targeted gene disruption in animals may unveil important biological functions, they also have limits, especially when the knockout is lethal during early embryogenesis. Recently, the study of ES cells bearing disrupted MAPK genes revealed that no role could been assigned to these pathways in undifferentiated ES cells, as MAPK pathways are apparently dispensable for ES cell self-renewal and cell cycle (see below). By contrast, new biological functions can be attributed to these proteins in the modulation of ES cell lineage commitment, which is the subject of the subsequent sections of this review.) S3 C. j B3 o/ d
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THE ERK PATHWAY
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Engagement of the gp130 cytokine receptor subunit by the LIF generates two intracellular signaling pathways: on one hand, the Janus tyrosine kinase-signal transducer and activator of transcription (STAT)3 pathway, which is required for ES self-renewal, and, on the other hand, the ERK pathway. Surprisingly and in contrast with most cultured cell lines, undifferentiated ES cells do not require the ERK pathway for normal cell cycle, proliferation, and self-renewal . g8 @% ?: s) C' p; Q
+ T4 F6 p ^, w8 v# G1 _The dominant role of the ERK pathway becomes apparent upon differentiation, both in vivo and in vitro. Interfering with the ERK signaling pathway, for example by knockout of the upstream activator Grb2, leads to inhibition of primitive endoderm . To gain genetic evidence of the role of ERK1 in adipocyte differentiation of ES cells and to analyze its function in other cell lineages, it would be of interest to generate and test the differentiation capacities of ERK1¨C/¨C ES cells.
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Interestingly, although ERK1¨C/¨C mice are viable and fertile . These findings confirm the direct role of the ERK pathway early during the embryonic development. Furthermore, they demonstrate that ERK1 and ERK2 have distinct biological functions. Although, as expected, ERK2 disruption does not interfere with proliferation of undifferentiated ES cells, no apparent mesoderm-derived lineages can be observed upon ES commitment (B. Bin¨¦truy and F. Bost, personal observation), suggesting that ERK2 is necessary at an early step of ES cell commitment. Since ERK1¨C/¨C mice present normal mesoderm differentiation (except for adipocyte formation), it is likely that the defect of ERK2¨C/¨C ES cells in mesoderm commitment takes place earlier than the defective adipogenesis of ERK1¨C/¨C cells.' V4 d' p2 d: G! g9 `
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Many defined ERK substrates are transcriptional regulators (reviewed in .
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4 ]6 q# w- ?/ |8 c& b% DTHE P38MAPK PATHWAY
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Among the four p38MAPK isoforms, , ¦Â, , and , only the knockout of p38 is embryonic lethal .4 b4 w) n- O R: ]+ q' ~+ H6 v
' V1 n/ N2 Q6 B; W2 n6 V# N+ sInterestingly, 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 .
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5 L9 K2 N/ v; P6 o) z9 lIn PC12 and P19 cell lines, p38MAPK activation is required for neurite formation and neuron survival during late stages of differentiation .4 z* }/ g- s( B# j
) F( k+ y# w- H0 O% ]Altogether, these results suggest that p38MAPK may exert different roles depending on the stage of neuronal differentiation: inhibitory during cell commitment and antiapoptotic 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.
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THE JNK PATHWAY; ?" ]) x5 I) U+ Z: T( Y
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Whereas single knockout of individual JNK genes has no effect on mice, jnk1¨C/¨Cjnk2¨C/¨C mice undergo midgestational embryonic lethality associated with defects in neural tube closure and deregulated neural apoptosis . Thus, these studies support a model where JNK1 activity represses a Wnt-4/Wnt-6 and BMP4 signaling axis that would otherwise direct the cells toward an epithelial lineage.
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The earliest two extraembryonic cell lineages are the trophectoderm and the primitive endoderm, which will form the placenta and yolk sac, respectively. Following implantation of early mammalian embryos, primitive endoderm differentiates to visceral endoderm and parietal endoderm; these tissues reside on the periphery of embryoid bodies formed in vitro by ES cells and embryonal carcinoma cells. Several groups have used P19 cells to unveil the requirement of a JNK signaling pathway in the retinoic acid-stimulated differentiation of these cells to primitive endoderm lineages demonstrated that the G13-interacting JNK pathway scaffold protein, JNK-interacting leucine zipper protein, is markedly induced by retinoic acid in P19 cells. Thus, a key regulatory step in retinoic acid-stimulated primitive endoderm differentiation appears to be the increased expression of a specific scaffold protein to assemble a G13-stimulated JNK module.; _+ N, K: e& J2 q9 [- L% P& O
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CONCLUSIONS AND PERSPECTIVE: z) [/ b5 a- Y- o5 z. l& X
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MAPK pathways are able to regulate both the early embryonic development and the ES cell commitment from early steps of the process to mature differentiated cells (the various effects are summarized in Fig. 2). The ERK pathway is mainly involved in mesoderm differentiation, especially in adipogenesis, with both positive and negative effects. p38MAPK displays a large spectrum of action from neurons to adipocytes, and JNK is involved in both ectoderm and primitive endoderm differentiations. Furthermore, for a given pathway, these effects are isoform-dependent, revealing the complexity of the cellular response to activation of these pathways. Notably, several lineages tested are affected by more than one transduction pathway. Adipogenesis is controlled by both ERK and p38MAPK, and neurogenesis is controlled by both p38MAPK and JNK. These observations are reminiscent of our recent studies in PC12 pheochromocytoma cells, indicating that complex differentiation programs such as neurogenesis will involve the integration of multiple signal pathways . Thus, it is equally likely that distinct ES cell lineage commitment programs will be regulated through the integrated action of two or more MAPK families. Cross talks between MAPK pathways can be either synergistic-ERK/JNK in neural differentiation of PC12¨C or antagonistic-p38MAPK/ERK in adipocyte differentiation of ES cells. Yet, taking advantage of the availability of the various MAPK-disrupted ES cell lines, the role of MAPKs in differentiation of numerous other cell types needs to be investigated.* E9 u0 L6 L7 o* [2 @
6 B* X2 h3 i. r" ?( r4 XFigure 2. Proposed model for the in vivo and in vitro mitogen-activated protein kinase effects on development (in italics) and embryonic stem cell differentiation. This model is deducted from the literature (see text). Abbreviations: ERK, extracellular signal-regulated kinase; JNK, c-Jun amino-terminal kinase.
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9 e" e+ j, h( ~! [ \) CAlthough the precise molecular mechanisms underlying the various MAPK functions in ES cell commitment are unknown, they must eventually lead to activation of cell lineage-specific genetic programs. Recently, important features of regulation of gene expression in ES cells have been unveiled. In undifferentiated mouse and human ES cells, the transcriptional repressors polycomb group proteins (PcG) repress numerous developmental regulators that, once derepressed, are able to trigger ES cells to undergo differentiation . Yet, we do not know whether this regulation is related to the biological role of MAPKs in ES cell commitment.! J) k4 u: A! Q5 t# Z5 `# z, o
$ c; X/ k7 T( F6 b0 U+ {Dominant signal pathways that control ES cell lineage commitment in vitro do not always translate to critical roles for these MAPK pathways unveiled with gene knockout approaches during mouse development. As an example, JNK1-deficient ES cells fail to undergo neurogenesis . In conclusion, despite the fact that not all ES cell findings may directly translate to dominant mechanisms of cell fate specification during development, they provide a highly valuable foundation of knowledge as tissue propagation from ES cells emerges as a discipline distinct from developmental biology.
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DISCLOSURE OF POTENTIAL CONFLICTS OF INTEREST9 ?; S- e5 y' o3 E- {9 e& z) A7 v
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The authors indicate no potential conflicts of interest.5 V f C- h; i6 X4 j! r( F# E
1 p9 v( H$ x" r1 t! n4 E" U; v& SACKNOWLEDGMENTS! a% D+ |0 ~' S/ u: d- N/ v& C# i, J
; c# R" P. n8 l+ c" \+ KWe thank F. Peiretti for critical reading of the manuscript. L.C. and M.A. were supported by fellowships from Institut National de la Sante et de la Recherche M¨¦dicale-Provence Alpes Cote d'Azur.( X( Z x. m5 w' [/ b0 _, V ~" k
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