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Concurrent BMP7 and FGF9 signalling governs AP-1 function to promote self-renewal of nephron progenitor cells.

ABSTRACT: Self-renewal of nephron progenitor cells (NPCs) is governed by BMP, FGF and WNT signalling. Mechanisms underlying cross-talk between these pathways at the molecular level are largely unknown. Here we delineate the pathway through which the proliferative BMP7 signal is transduced in NPCs in the mouse. BMP7 activates the MAPKs TAK1 and JNK to phosphorylate the transcription factor JUN, which in turn governs transcription of AP-1-element containing G1-phase cell cycle regulators such as Myc and Ccnd1 to promote NPC proliferation. Conditional inactivation of Tak1 or Jun in cap mesenchyme causes identical phenotypes characterized by premature depletion of NPCs. While JUN is regulated by BMP7, we find that its partner FOS is regulated by FGF9. We demonstrate that BMP7 and FGF9 coordinately regulate AP-1 transcription to promote G1-S cell cycle progression and NPC proliferation. Our findings identify a molecular mechanism explaining the important cooperation between two major NPC self-renewal pathways.

SUBMITTER: Muthukrishnan SD

PROVIDER: S-EPMC4686668 | biostudies-literature | 2015 Dec

REPOSITORIES: biostudies-literature

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Concurrent BMP7 and FGF9 signalling governs AP-1 function to promote self-renewal of nephron progenitor cells.

Muthukrishnan Sree Deepthi SD Yang Xuehui X Friesel Robert R Oxburgh Leif L

Nature communications 20151204

Self-renewal of nephron progenitor cells (NPCs) is governed by BMP, FGF and WNT signalling. Mechanisms underlying cross-talk between these pathways at the molecular level are largely unknown. Here we delineate the pathway through which the proliferative BMP7 signal is transduced in NPCs in the mouse. BMP7 activates the MAPKs TAK1 and JNK to phosphorylate the transcription factor JUN, which in turn governs transcription of AP-1-element containing G1-phase cell cycle regulators such as Myc and Ccn ...[more]

PMID: 26634297

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Project description:Many acute and chronic anaemias, including haemolysis, sepsis and genetic bone marrow failure diseases such as Diamond-Blackfan anaemia, are not treatable with erythropoietin (Epo), because the colony-forming unit erythroid progenitors (CFU-Es) that respond to Epo are either too few in number or are not sensitive enough to Epo to maintain sufficient red blood cell production. Treatment of these anaemias requires a drug that acts at an earlier stage of red cell formation and enhances the formation of Epo-sensitive CFU-E progenitors. Recently, we showed that glucocorticoids specifically stimulate self-renewal of an early erythroid progenitor, burst-forming unit erythroid (BFU-E), and increase the production of terminally differentiated erythroid cells. Here we show that activation of the peroxisome proliferator-activated receptor ? (PPAR-?) by the PPAR-? agonists GW7647 and fenofibrate synergizes with the glucocorticoid receptor (GR) to promote BFU-E self-renewal. Over time these agonists greatly increase production of mature red blood cells in cultures of both mouse fetal liver BFU-Es and mobilized human adult CD34(+) peripheral blood progenitors, with a new and effective culture system being used for the human cells that generates normal enucleated reticulocytes. Although Ppara(-/-) mice show no haematological difference from wild-type mice in both normal and phenylhydrazine (PHZ)-induced stress erythropoiesis, PPAR-? agonists facilitate recovery of wild-type but not Ppara(-/-) mice from PHZ-induced acute haemolytic anaemia. We also show that PPAR-? alleviates anaemia in a mouse model of chronic anaemia. Finally, both in control and corticosteroid-treated BFU-E cells, PPAR-? co-occupies many chromatin sites with GR; when activated by PPAR-? agonists, additional PPAR-? is recruited to GR-adjacent sites and presumably facilitates GR-dependent BFU-E self-renewal. Our discovery of the role of PPAR-? agonists in stimulating self-renewal of early erythroid progenitor cells suggests that the clinically tested PPAR-? agonists we used may improve the efficacy of corticosteroids in treating Epo-resistant anaemias.

Dataset Information

Concurrent BMP7 and FGF9 signalling governs AP-1 function to promote self-renewal of nephron progenitor cells.

Publications

Concurrent BMP7 and FGF9 signalling governs AP-1 function to promote self-renewal of nephron progenitor cells.

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