Journal
NATURE COMMUNICATIONS
Volume 6, Issue -, Pages -Publisher
NATURE PUBLISHING GROUP
DOI: 10.1038/ncomms10027
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Funding
- National Institute of General Medicine (NIGMS) [5P30 GM106391]
- National Institute of Histopathology [NIGMS 5P30 GM106391, 5P30 GM103392]
- National Institute of Transgenics and Gene Targeting [NIGMS 5P30 GM103392]
- National Institute of Cell Culture /Viral Vectors [NIGMS 5P30 GM103392]
- National Institutes of Diabetes and Digestive and Kidney Disease [R01DK078161]
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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.
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