ESC self-renewal and pluripotency in mouse are regulated by extrinsic and intrinsic factors. Extrinsic factors include LIF, BMP and WNT while the intrinsic machinery includes the transcription factors Oct4, Nanog and SOX2. LIF signaling is a major pathway contributing to mouse ESC pluripotency. LIF signals through the heterodimerization of LIFR and GP130 receptors. On binding LIF, the LIFR-GP130 heterodimer recruits JAK to phosphorylate STAT3. Phosphorylated STAT3 translocates to the nucleus and induces Oct4 and c-Myc transcription. LIF also activates the Ras/ERK signaling pathway through the effector protein SHP2. LIF-induced STAT3 activation promotes self-renewal, whereas LIF-induced ERK activation promotes differentiation. Phosphorylated JAK also activates the PI3K/AKT pathway which can also be activated endogenously by Eras.BMP4 is another extrinsic factor known to support mouse ESC self-renewal. In the presence of LIF, BMP4 activates the SMAD transcription factors. BMP4 binds to its receptor complex (BMPRII-ALK3) through which it induces the phosphorylation of SMAD1 and SMAD5. These phosphorylated SMADs then form a complex with SMAD4 and translocate into the nucleus to activate transcription of ID genes known to be involved in cell fate determination. ALK3 also dephosphorylates p38 MAPK and ERK and inactivates them. In the absence of LIF, low concentrations of BMPs promote mesoderm differentiation of mouse ES cells. In the presence of LIF, activated STAT3 interacts with T and causes up regulation of Nanog, leading to pluripotency.
The canonical WNT pathway is activated on binding of WNT to the Frizzled receptor, which leads to inhibition of GSK3β. Subsequent nuclear accumulation of CTNN-β is followed by its association with LEF/TCF and CBP, and causes expression of target genes such as c-Myc, Oct4, Rex1 and STAT5, all critical for stem cell proliferation. GSK3β also negatively regulates c-Myc activity by phosphorylation and subsequent degradation by the proteasome system. Thus, extrinsic and intrinsic factors work together to determine mouse ESC renewal and pluripotency.