Analysis of Ret knockin mice reveals a critical role for IKKs, but not PI 3-K, in neurotrophic factor-induced survival of sympathetic neurons.

Encinas Martín, Mario; Rozen, Esteban Javier; Dolcet Roca, Xavier; Jain, Sanjay; Comella i Carnicé, Joan Xavier; Milbrandt, Jeffrey; Johnson, Eugene M.

doi:https://doi.org/10.1038/cdd.2008.76

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2008

Author

Encinas Martín, Mario

Rozen, Esteban Javier

Dolcet Roca, Xavier

Jain, Sanjay

Comella i Carnicé, Joan Xavier

Milbrandt, Jeffrey

Johnson, Eugene M.

Abstract

We analyzed the survival responses and downstream signaling elicited by GDNF on sympathetic neurons from different Ret knockin mice. Lack of tyrosine 1062, a multidocking site in Ret, completely prevented GDNF-mediated survival. Importantly lack of tyrosine 981, although abrogating Akt phosphorylation,

had no effect on neuronal survival, indicating that the PI 3-K/Akt pathway is not necessary for survival of sympathetic neurons. In contrast, silencing of B-Raf completely prevented not only GDNF-mediated but also NGF-mediated cell survival, independently of MEK-1/2. We identified IKKs as the main effectors of the protective effects of B-Raf. First, BRaf interacted with and activated IKKs. Second, knockdown of IKKs reversed the protection afforded by a constitutively active form of B-Raf. Third, knockdown of IKKs prevented both NGF- and GDNF-mediated survival. In conclusion, our data delineate a novel survival pathway for sympathetic neurons linking B-Raf to IKKs, independently of both PI 3-K and MEK-1/2 pathways.