Date of Award

Spring 5-14-2016

Level of Access Assigned by Author

Open-Access Thesis

Degree Name

Doctor of Philosophy (PhD)

Department

Biomedical Sciences

Advisor

Leif Oxburgh

Second Committee Member

Robert Friesel

Third Committee Member

Calvin Vary

Abstract

Self-renewal and differentiation of nephron progenitor cells (NPCs) in the developing kidney is governed by three major growth factor pathways: BMP, FGF and WNT. Mechanisms underlying the cross-talk between these pathways at the molecular level are largely unknown.

In this study, we demonstrate that BMP7 activates SMAD1/5 signaling in the distal region of the cap mesenchyme (CM) to promote the transition of early CITED1+ NPCs into the SIX2-only compartment. BMP7-mediated SMAD1/5 signaling synergizes with WNT9b-β-catenin signaling in SIX2-only cells to induce the pro-differentiation program via Wnt4 activation. We show that the pharmacological inhibition of SMAD1/5 signaling retains the NPCs in the CITED1+ progenitor state, delays cessation of nephrogenesis and increases nephron endowment in mice.

We also delineate the pathway through which the proliferative BMP7 signal is transduced in CITED1+ NPCs. BMP7 activates the MAPKs TAK1 and JNK to phosphorylate the transcription factor JUN, which in turn governs the transcription of an 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 the 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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