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Sall1 in renal stromal progenitors non-cell autonomously restricts the excessive expansion of nephron progenitors.

Ohmori T, Tanigawa S, Kaku Y, Fujimura S, Nishinakamura R - Sci Rep (2015)

Bottom Line: We found that Decorin, which inhibits Bmp-mediated nephron differentiation, was upregulated in the mutant stroma.In contrast, the expression of Fat4, which restricts nephron progenitor expansion, was reduced mildly.Thus, the expression of Sall1 in stromal progenitors restricts the excessive expansion of nephron progenitors in a non-cell autonomous manner, and Sall1-mediated regulation of Decorin and Fat4 might at least partially underlie the pathogenesis.

View Article: PubMed Central - PubMed

Affiliation: Department of Kidney Development, Institute of Molecular Embryology and Genetics, Kumamoto University, 2-2-1 Honjo, Kumamoto 860-0811, Japan.

ABSTRACT
The mammalian kidney develops from reciprocal interactions between the metanephric mesenchyme and ureteric bud, the former of which contains nephron progenitors. The third lineage, the stroma, fills up the interstitial space and is derived from distinct progenitors that express the transcription factor Foxd1. We showed previously that deletion of the nuclear factor Sall1 in nephron progenitors leads to their depletion in mice. However, Sall1 is expressed not only in nephron progenitors but also in stromal progenitors. Here we report that specific Sall1 deletion in stromal progenitors leads to aberrant expansion of nephron progenitors, which is in sharp contrast with a nephron progenitor-specific deletion. The mutant mice also exhibited cystic kidneys after birth and died before adulthood. We found that Decorin, which inhibits Bmp-mediated nephron differentiation, was upregulated in the mutant stroma. In contrast, the expression of Fat4, which restricts nephron progenitor expansion, was reduced mildly. Furthermore, the Sall1 protein binds to many stroma-related gene loci, including Decorin and Fat4. Thus, the expression of Sall1 in stromal progenitors restricts the excessive expansion of nephron progenitors in a non-cell autonomous manner, and Sall1-mediated regulation of Decorin and Fat4 might at least partially underlie the pathogenesis.

No MeSH data available.


Related in: MedlinePlus

Nephron progenitors are expanded in the Sall1 mutant kidney.(A–C) Dual immunostaining for Sall1 (red) and Six2 (green) in Sall1flox/flox and Foxd1Cre; Sall1flox/flox kidneys at E12.5. Sall1 expression in the stroma (arrowheads) is absent but is retained in the nephron progenitors (arrows) that are positive for Six2. ub: ureteric bud. (D) Immunostaining for Sall1 (red) and Aldh1a2 (green) of Sall1flox/flox and Foxd1GFPCre; Sall1flox/flox kidneys at E12.5. Note the absence of Sall1 in the Aldh1a2-positive stromal cells (arrows). (E,F) Dual immunostaining for Six2 (red) and Aldh1a2 (green) at E14.5. Six2-positive nephron progenitors (arrows) are expanded, while Aldh1a2-positive stromal cells (arrowheads) are retained in the mutant kidney. Some stromal cells (asterisks) reach the ureteric bud (ub) tip epithelium in the control. (G) Dual immunostaining for Six2 (green) and Ncam (red) at E14.5. Nephron progenitors are expanded, but the Ncam-positive nascent nephrons (yellow arrowheads) are formed. Scale bars = 20 μm.
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f3: Nephron progenitors are expanded in the Sall1 mutant kidney.(A–C) Dual immunostaining for Sall1 (red) and Six2 (green) in Sall1flox/flox and Foxd1Cre; Sall1flox/flox kidneys at E12.5. Sall1 expression in the stroma (arrowheads) is absent but is retained in the nephron progenitors (arrows) that are positive for Six2. ub: ureteric bud. (D) Immunostaining for Sall1 (red) and Aldh1a2 (green) of Sall1flox/flox and Foxd1GFPCre; Sall1flox/flox kidneys at E12.5. Note the absence of Sall1 in the Aldh1a2-positive stromal cells (arrows). (E,F) Dual immunostaining for Six2 (red) and Aldh1a2 (green) at E14.5. Six2-positive nephron progenitors (arrows) are expanded, while Aldh1a2-positive stromal cells (arrowheads) are retained in the mutant kidney. Some stromal cells (asterisks) reach the ureteric bud (ub) tip epithelium in the control. (G) Dual immunostaining for Six2 (green) and Ncam (red) at E14.5. Nephron progenitors are expanded, but the Ncam-positive nascent nephrons (yellow arrowheads) are formed. Scale bars = 20 μm.

Mentions: Next, we analysed the mutant mice during gestation. At embryonic day (E) 12.5, Sall1 was expressed not only in Six2-positive nephron progenitors but also in the surrounding stroma in the controls (Fig. 3A–C, Supplementary Fig. S1), as we reported previously20. Sall1 expression in the stroma disappeared in the Foxd1Cre; Sall1flox/flox kidney, and was restricted to the Six2-positive domain (Fig. 3A–C). Co-immunostaining for the stromal marker Aldh1a2 (also known as retinoic acid dehydrogenase 2: Raldh2)22 also showed the absence of Sall1 in the stromal cells (Fig. 3D). Because Foxd1Cre mice express a fusion protein of Green Fluorescent Protein (GFP) and Cre recombinase, GFP was detected in the stromal progenitors surrounding the nephron progenitors, and Sall1 was absent in the former population (Supplementary Fig. S1).


Sall1 in renal stromal progenitors non-cell autonomously restricts the excessive expansion of nephron progenitors.

Ohmori T, Tanigawa S, Kaku Y, Fujimura S, Nishinakamura R - Sci Rep (2015)

Nephron progenitors are expanded in the Sall1 mutant kidney.(A–C) Dual immunostaining for Sall1 (red) and Six2 (green) in Sall1flox/flox and Foxd1Cre; Sall1flox/flox kidneys at E12.5. Sall1 expression in the stroma (arrowheads) is absent but is retained in the nephron progenitors (arrows) that are positive for Six2. ub: ureteric bud. (D) Immunostaining for Sall1 (red) and Aldh1a2 (green) of Sall1flox/flox and Foxd1GFPCre; Sall1flox/flox kidneys at E12.5. Note the absence of Sall1 in the Aldh1a2-positive stromal cells (arrows). (E,F) Dual immunostaining for Six2 (red) and Aldh1a2 (green) at E14.5. Six2-positive nephron progenitors (arrows) are expanded, while Aldh1a2-positive stromal cells (arrowheads) are retained in the mutant kidney. Some stromal cells (asterisks) reach the ureteric bud (ub) tip epithelium in the control. (G) Dual immunostaining for Six2 (green) and Ncam (red) at E14.5. Nephron progenitors are expanded, but the Ncam-positive nascent nephrons (yellow arrowheads) are formed. Scale bars = 20 μm.
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f3: Nephron progenitors are expanded in the Sall1 mutant kidney.(A–C) Dual immunostaining for Sall1 (red) and Six2 (green) in Sall1flox/flox and Foxd1Cre; Sall1flox/flox kidneys at E12.5. Sall1 expression in the stroma (arrowheads) is absent but is retained in the nephron progenitors (arrows) that are positive for Six2. ub: ureteric bud. (D) Immunostaining for Sall1 (red) and Aldh1a2 (green) of Sall1flox/flox and Foxd1GFPCre; Sall1flox/flox kidneys at E12.5. Note the absence of Sall1 in the Aldh1a2-positive stromal cells (arrows). (E,F) Dual immunostaining for Six2 (red) and Aldh1a2 (green) at E14.5. Six2-positive nephron progenitors (arrows) are expanded, while Aldh1a2-positive stromal cells (arrowheads) are retained in the mutant kidney. Some stromal cells (asterisks) reach the ureteric bud (ub) tip epithelium in the control. (G) Dual immunostaining for Six2 (green) and Ncam (red) at E14.5. Nephron progenitors are expanded, but the Ncam-positive nascent nephrons (yellow arrowheads) are formed. Scale bars = 20 μm.
Mentions: Next, we analysed the mutant mice during gestation. At embryonic day (E) 12.5, Sall1 was expressed not only in Six2-positive nephron progenitors but also in the surrounding stroma in the controls (Fig. 3A–C, Supplementary Fig. S1), as we reported previously20. Sall1 expression in the stroma disappeared in the Foxd1Cre; Sall1flox/flox kidney, and was restricted to the Six2-positive domain (Fig. 3A–C). Co-immunostaining for the stromal marker Aldh1a2 (also known as retinoic acid dehydrogenase 2: Raldh2)22 also showed the absence of Sall1 in the stromal cells (Fig. 3D). Because Foxd1Cre mice express a fusion protein of Green Fluorescent Protein (GFP) and Cre recombinase, GFP was detected in the stromal progenitors surrounding the nephron progenitors, and Sall1 was absent in the former population (Supplementary Fig. S1).

Bottom Line: We found that Decorin, which inhibits Bmp-mediated nephron differentiation, was upregulated in the mutant stroma.In contrast, the expression of Fat4, which restricts nephron progenitor expansion, was reduced mildly.Thus, the expression of Sall1 in stromal progenitors restricts the excessive expansion of nephron progenitors in a non-cell autonomous manner, and Sall1-mediated regulation of Decorin and Fat4 might at least partially underlie the pathogenesis.

View Article: PubMed Central - PubMed

Affiliation: Department of Kidney Development, Institute of Molecular Embryology and Genetics, Kumamoto University, 2-2-1 Honjo, Kumamoto 860-0811, Japan.

ABSTRACT
The mammalian kidney develops from reciprocal interactions between the metanephric mesenchyme and ureteric bud, the former of which contains nephron progenitors. The third lineage, the stroma, fills up the interstitial space and is derived from distinct progenitors that express the transcription factor Foxd1. We showed previously that deletion of the nuclear factor Sall1 in nephron progenitors leads to their depletion in mice. However, Sall1 is expressed not only in nephron progenitors but also in stromal progenitors. Here we report that specific Sall1 deletion in stromal progenitors leads to aberrant expansion of nephron progenitors, which is in sharp contrast with a nephron progenitor-specific deletion. The mutant mice also exhibited cystic kidneys after birth and died before adulthood. We found that Decorin, which inhibits Bmp-mediated nephron differentiation, was upregulated in the mutant stroma. In contrast, the expression of Fat4, which restricts nephron progenitor expansion, was reduced mildly. Furthermore, the Sall1 protein binds to many stroma-related gene loci, including Decorin and Fat4. Thus, the expression of Sall1 in stromal progenitors restricts the excessive expansion of nephron progenitors in a non-cell autonomous manner, and Sall1-mediated regulation of Decorin and Fat4 might at least partially underlie the pathogenesis.

No MeSH data available.


Related in: MedlinePlus