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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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PI3K/Akt Signaling Is Necessary for ENP Self-Renewal and Kidney Development(A) E12.5 kidneys cultured for 48 hr. Arrowheads point to nephrons.(B) Measurements of kidney area and nephron tubule widths from kidneys. Nine and eight separate kidneys and 76 and 53 nephrons were analyzed for control and Ly294002 conditions, respectively. Error bars indicate SEM. Significance calculated using Student’s t test.(C and D) Kidneys cultured for 24 hr. Arrowheads indicate nephron progenitors.(E) Time-lapse data for E11.5 Six2+/GCiP;Rosa26tdRFP kidneys cultured for 69 hr. White dashed line indicates generations of nephrons forming. Cm, cap mesenchyme containing ENPs; pta, pretubular aggregate; rv, renal vesicle; sb, s-shaped body; ub, ureteric bud; ubt, ureteric bud tip. Culture conditions and labeling are as indicated in figures. See also Figure S1.
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fig1: PI3K/Akt Signaling Is Necessary for ENP Self-Renewal and Kidney Development(A) E12.5 kidneys cultured for 48 hr. Arrowheads point to nephrons.(B) Measurements of kidney area and nephron tubule widths from kidneys. Nine and eight separate kidneys and 76 and 53 nephrons were analyzed for control and Ly294002 conditions, respectively. Error bars indicate SEM. Significance calculated using Student’s t test.(C and D) Kidneys cultured for 24 hr. Arrowheads indicate nephron progenitors.(E) Time-lapse data for E11.5 Six2+/GCiP;Rosa26tdRFP kidneys cultured for 69 hr. White dashed line indicates generations of nephrons forming. Cm, cap mesenchyme containing ENPs; pta, pretubular aggregate; rv, renal vesicle; sb, s-shaped body; ub, ureteric bud; ubt, ureteric bud tip. Culture conditions and labeling are as indicated in figures. See also Figure S1.

Mentions: To examine the role of PI3K during ENP self-renewal and differentiation, we blocked PI3K with LY294002 in kidney organ cultures. Treatment of kidney rudiments with this compound for 48 hr visually disturbed branching of the ureteric bud as described before (Tang et al., 2002; Figure 1A). PI3K inhibition resulted in reduced kidney size, but nephrons with increased diameter (Figure 1B) and a thinning of the SIX2+ ENP-containing cap mesenchyme (Figures 1A and 1C; Self et al., 2006) after blocking PI3K for just 24 hr, a time point when branching was still unaffected (not shown). We confirmed this phenotype using a second, structurally dissimilar PI3K inhibitor, GDC-0941 (Figures S1A–S1E; Table S1). Reduced staining for mTORC1 pSer2448 and AKT pSer473 confirmed the inhibition of the PI3K pathway by LY294002 (Figures S1F and S1G).


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)

PI3K/Akt Signaling Is Necessary for ENP Self-Renewal and Kidney Development(A) E12.5 kidneys cultured for 48 hr. Arrowheads point to nephrons.(B) Measurements of kidney area and nephron tubule widths from kidneys. Nine and eight separate kidneys and 76 and 53 nephrons were analyzed for control and Ly294002 conditions, respectively. Error bars indicate SEM. Significance calculated using Student’s t test.(C and D) Kidneys cultured for 24 hr. Arrowheads indicate nephron progenitors.(E) Time-lapse data for E11.5 Six2+/GCiP;Rosa26tdRFP kidneys cultured for 69 hr. White dashed line indicates generations of nephrons forming. Cm, cap mesenchyme containing ENPs; pta, pretubular aggregate; rv, renal vesicle; sb, s-shaped body; ub, ureteric bud; ubt, ureteric bud tip. Culture conditions and labeling are as indicated in figures. See also Figure S1.
© Copyright Policy - CC BY
Related In: Results  -  Collection

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getmorefigures.php?uid=PMC4400645&req=5

fig1: PI3K/Akt Signaling Is Necessary for ENP Self-Renewal and Kidney Development(A) E12.5 kidneys cultured for 48 hr. Arrowheads point to nephrons.(B) Measurements of kidney area and nephron tubule widths from kidneys. Nine and eight separate kidneys and 76 and 53 nephrons were analyzed for control and Ly294002 conditions, respectively. Error bars indicate SEM. Significance calculated using Student’s t test.(C and D) Kidneys cultured for 24 hr. Arrowheads indicate nephron progenitors.(E) Time-lapse data for E11.5 Six2+/GCiP;Rosa26tdRFP kidneys cultured for 69 hr. White dashed line indicates generations of nephrons forming. Cm, cap mesenchyme containing ENPs; pta, pretubular aggregate; rv, renal vesicle; sb, s-shaped body; ub, ureteric bud; ubt, ureteric bud tip. Culture conditions and labeling are as indicated in figures. See also Figure S1.
Mentions: To examine the role of PI3K during ENP self-renewal and differentiation, we blocked PI3K with LY294002 in kidney organ cultures. Treatment of kidney rudiments with this compound for 48 hr visually disturbed branching of the ureteric bud as described before (Tang et al., 2002; Figure 1A). PI3K inhibition resulted in reduced kidney size, but nephrons with increased diameter (Figure 1B) and a thinning of the SIX2+ ENP-containing cap mesenchyme (Figures 1A and 1C; Self et al., 2006) after blocking PI3K for just 24 hr, a time point when branching was still unaffected (not shown). We confirmed this phenotype using a second, structurally dissimilar PI3K inhibitor, GDC-0941 (Figures S1A–S1E; Table S1). Reduced staining for mTORC1 pSer2448 and AKT pSer473 confirmed the inhibition of the PI3K pathway by LY294002 (Figures S1F and S1G).

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