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The PI3K pathway balances self-renewal and differentiation of nephron progenitor cells through β-catenin signaling.

Lindström NO, Carragher NO, Hohenstein P - Stem Cell Reports (2015)

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.

View Article: PubMed Central - PubMed

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: nils.lindstrom@roslin.ed.ac.uk.

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Multiple Signaling Pathways Feed into PI3K-Dependent ENP Self-Renewal(A) E12.5 kidneys cultured for 48 hr. White arrowheads indicate ectopic ENP differentiation.(B) Time-lapse data showing E12.5 TCF/Lef::H2B-GFP kidneys cultured for 48 hr. The GFP signal is shown as a heat map. Blue arrowheads indicate ectopic GFP+ nuclei; black dashed line outlines the ureteric bud and normally positioned nephrogenic epithelium; blue dashed line outlines ectopic regions with strong GFP signal.(C) Schematic model for PI3K signaling in ENP cells. The relationship of different signaling pathways is depicted and related to their outcomes in ENP cells. Culture conditions and labeling are as indicated in figures.
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fig4: Multiple Signaling Pathways Feed into PI3K-Dependent ENP Self-Renewal(A) E12.5 kidneys cultured for 48 hr. White arrowheads indicate ectopic ENP differentiation.(B) Time-lapse data showing E12.5 TCF/Lef::H2B-GFP kidneys cultured for 48 hr. The GFP signal is shown as a heat map. Blue arrowheads indicate ectopic GFP+ nuclei; black dashed line outlines the ureteric bud and normally positioned nephrogenic epithelium; blue dashed line outlines ectopic regions with strong GFP signal.(C) Schematic model for PI3K signaling in ENP cells. The relationship of different signaling pathways is depicted and related to their outcomes in ENP cells. Culture conditions and labeling are as indicated in figures.

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.


The PI3K pathway balances self-renewal and differentiation of nephron progenitor cells through β-catenin signaling.

Lindström NO, Carragher NO, Hohenstein P - Stem Cell Reports (2015)

Multiple Signaling Pathways Feed into PI3K-Dependent ENP Self-Renewal(A) E12.5 kidneys cultured for 48 hr. White arrowheads indicate ectopic ENP differentiation.(B) Time-lapse data showing E12.5 TCF/Lef::H2B-GFP kidneys cultured for 48 hr. The GFP signal is shown as a heat map. Blue arrowheads indicate ectopic GFP+ nuclei; black dashed line outlines the ureteric bud and normally positioned nephrogenic epithelium; blue dashed line outlines ectopic regions with strong GFP signal.(C) Schematic model for PI3K signaling in ENP cells. The relationship of different signaling pathways is depicted and related to their outcomes in ENP cells. Culture conditions and labeling are as indicated in figures.
© Copyright Policy - CC BY
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC4400645&req=5

fig4: Multiple Signaling Pathways Feed into PI3K-Dependent ENP Self-Renewal(A) E12.5 kidneys cultured for 48 hr. White arrowheads indicate ectopic ENP differentiation.(B) Time-lapse data showing E12.5 TCF/Lef::H2B-GFP kidneys cultured for 48 hr. The GFP signal is shown as a heat map. Blue arrowheads indicate ectopic GFP+ nuclei; black dashed line outlines the ureteric bud and normally positioned nephrogenic epithelium; blue dashed line outlines ectopic regions with strong GFP signal.(C) Schematic model for PI3K signaling in ENP cells. The relationship of different signaling pathways is depicted and related to their outcomes in ENP cells. Culture conditions and labeling are as indicated in figures.
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.

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.

View Article: PubMed Central - PubMed

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: nils.lindstrom@roslin.ed.ac.uk.

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Related in: MedlinePlus