title: GDNF-independent ureteric budding: role of PI3K-independent activation of AKT and FOSB/JUN/AP-1 signaling.
abstract: A significant fraction of mice deficient in either glial cell-derived neurotrophic factor (GDNF) or its co-receptors (Gfrα1, Ret), undergoes ureteric bud (UB) outgrowth leading to the formation of a rudimentary kidney. Previous studies using the isolated Wolffian duct (WD) culture indicate that activation of fibroblast growth factor (FGF) receptor signaling, together with suppression of BMP/Activin signaling, is critical for GDNF-independent WD budding (Maeshima et al., 2007). By expression analysis of embryonic kidney from Ret((-/-)) mice, we found the upregulation of several FGFs, including FGF7. To examine the intracellular pathways, we then analyzed GDNF-dependent and GDNF-independent budding in the isolated WD culture. In both conditions, Akt activation was found to be important; however, whereas this occurred through PI3-kinase in GDNF-dependent budding, in the case of GDNF-independent budding, Akt activation was apparently via a PI3-kinase independent mechanism. Jnk signaling and the AP-1 transcription factor complex were also implicated in GDNF-independent budding. FosB, a binding partner of c-Jun in the formation of AP-1, was the most highly upregulated gene in the ret knockout kidney (in which budding had still occurred), and we found that its siRNA-mediated knockdown in isolated WDs also blocked GDNF-independent budding. Taken together with the finding that inhibition of Jnk signaling does not block Akt activation/phosphorylation in GDNF-independent budding, the data support necessary roles for both FosB/Jun/AP-1 signaling and PI3-kinase-independent activation of Akt in GDNF-independent budding. A model is proposed for signaling events that involve Akt and JNK working to regulate GDNF-independent WD budding.
authors.affiliation: Department of Medicine, University of California , San Diego, La Jolla, CA 92093-0693 , USA ; Present address: Department of Pediatrics, University of Calgary and Alberta Children's Hospital, Calgary, AB T3B 6A8, Canada.
authors.forename: James B
authors.initials: JB
authors.lastname: Tee
authors.forename: Yohan
authors.initials: Y
authors.lastname: Choi
authors.forename: Ankur
authors.initials: A
authors.lastname: Dnyanmote
authors.forename: Marvalyn
authors.initials: M
authors.lastname: Decambre
authors.forename: Chiharu
authors.initials: C
authors.lastname: Ito
authors.forename: Kevin T
authors.initials: KT
authors.lastname: Bush
authors.forename: Sanjay K
authors.initials: SK
authors.lastname: Nigam
keywords: AKT; Fibroblast growth factor; JNK signaling; Jun-Fos; Kidney development; Ureteric bud; Wolffian duct; ret