The PI3K pathway balances self-renewal and differentiation of nephron progenitor cells through β-catenin signaling.
Bottom Line: Nephron progenitor cells differentiate to form nephrons during embryonic kidney development.In contrast, self-renewal maintains progenitor numbers and premature depletion leads to impaired kidney function.Here we analyze the PI3K pathway as a point of convergence for the multiple pathways that are known to control self-renewal in the kidney.
Affiliation: The Roslin Institute, University of Edinburgh, Easter Bush Campus, Midlothian EH25 9RG, UK; Edinburgh Cancer Research Centre, MRC Institute of Genetics and Molecular Medicine, University of Edinburgh, Western General Hospital, Edinburgh EH4 2XR, UK. Electronic address: firstname.lastname@example.org.Show MeSH
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Mentions: BMP7/pSMAD signaling can switch ENPs from self-renewing to differentiating (Brown et al., 2013). We compared the effects of inhibiting PI3K signaling to blocking BMP receptors with LDN-193189. Blocking BMP signaling led to a loss of SIX2+ cells, similar to that seen in Bmp7-deficient animals (Brown et al., 2013), and disruption of branching morphogenesis, but did not trigger ectopic nephron formation; inhibition of PI3K still drove ectopic nephron formation and altered the growth of nephrons when BMP signaling was inhibited (Figure 4A). Inhibition of BMP signaling did not trigger increased β-catenin signaling in ENPs (Figure 4B; Movie S3), but simultaneous inhibition of BMP signaling and activation of β-catenin actually resulted in massive and rapid upregulation of β-catenin signaling in ENPs. Inhibiting PI3K and activating β-catenin at the same time also resulted in massive upregulation of β-catenin signaling in ENPs, but the dynamics of the ENP response to CHIR + LDN-193189 and CHIR + Ly294002 were different. ENPs with only CHIR activated β-catenin signaling slower than those in CHIR + LDN-193189, and the cells were more motile and migrated away from the ureteric bud tips. In CHIR + LDN-193189, β-catenin signaling was activated very quickly, to higher levels, and the cells remained surrounding the ureteric bud tips. In CHIR + Ly294002 conditions, β-catenin signaling was activated quicker than in CHIR-only conditions, but, similar to CHIR + LDN-193189 conditions, however, cells displayed motility (Movie S3). Although CHIR + LDN-193189 and CHIR + Ly294002 created distinct responses from each other, they both increased the activation of β-catenin signaling compared to CHIR.
Affiliation: The Roslin Institute, University of Edinburgh, Easter Bush Campus, Midlothian EH25 9RG, UK; Edinburgh Cancer Research Centre, MRC Institute of Genetics and Molecular Medicine, University of Edinburgh, Western General Hospital, Edinburgh EH4 2XR, UK. Electronic address: email@example.com.