The JNK pathway

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Whereas single knock-out of individual JNK genes have no effect on mice, jnk1^-/-jnk2^-/- mice undergo mid-gestational embryonic lethality associated with defects in neural tube closure and deregulated neural apoptosis [57, 58]. The deletion of JNK1, but not JNK2, leads to the resistance to high-fat diet induced obesity and the absence of JNK1 leads to a better insulin sensitivity attributed to a reduced phosphorylation of IRS-1 on Ser307 [59]. However, if the JNK pathway is involved in insulin signalling, there is no evidence for a role of this pathway in adipocyte differentiation. Similar to the ERK and p38 MAPK pathways, the JNK family of MAPKs are not required for self-renewal or maintenance of ES cells [8]. A variety of approaches have defined a role for the JNK pathway in differentiation of ES cells as well as P19 embryonal carcinoma cells to neural and extraembryonic endoderm lineages. We recently employed ES cells derived from mice bearing disrupted jnk1, jnk2 or jnk3 to define a requirement for JNK1 in retinoic acid-induced neurogenesis [8]. Importantly, the lack of neurogenesis by JNK1^-/- ES cells was associated with enhanced induction of an epithelial differentiation program evidenced by increased E-cadherin. In addition, the expression of Wnt-4, Wnt-6 and BMP4 were markedly increased in the JNK1^-/- cultures, consistent with a role for specific Wnts and BMP4 as members of a key lineage commitment switch in ES cell differentiation [60] [61] [7]. A role for the JNKs in neural differentiation of ES cells is consistent with the observation of similarly reduced neural differentiation in ES cells deficient for the JNK pathway scaffold protein, JSAP [62]. 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 towards an epithelial lineage.

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 signalling pathway in the retinoic acid-stimulated differentiation of these cells to primitive endoderm lineages [63]. In addition, our own recent studies reveal that retinoic acid-stimulated expression of a variety of visceral and parietal endoderm lineage markers (GATA4, GATA6, Sox17, disabled 2, a-fetoprotein) are inhibited in JNK1^-/- and JNK2^-/- ES cell-derived embryoid bodies (L. Heasley, unpublished observation). In the P19 cell model system, signaling by the heterotrimeric G protein, G₁₃, and stimulation of the activity of p115RhoGEF is required for primitive endoderm differentiation [64]. Moreover, a recent study by Kashef et al [65] demonstrated that the G₁₃-interacting JNK pathway scaffold protein, JLP, 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.