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.

Suggested citation

Encinas Martín, Mario; Rozen, Esteban Javier; Dolcet Roca, Xavier; Jain, Sanjay; Comella i Carnicé, Joan Xavier; Milbrandt, Jeffrey; Johnson, Eugene M.; . (2008) . Analysis of Ret knockin mice reveals a critical role for IKKs, but not PI 3-K, in neurotrophic factor-induced survival of sympathetic neurons.. Cell Death and Differentiation, 2008, vol. 15, núm. 9, p. 1510-1521. https://doi.org/10.1038/cdd.2008.76.

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.