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Basic Research Paper

Suppression of MAPK/JNK-MTORC1 signaling leads to premature loss of organelles and nuclei by autophagy during terminal differentiation of lens fiber cells

, , , &
Pages 1193-1211 | Received 21 Jun 2013, Accepted 03 Apr 2014, Published online: 09 May 2014
 

Abstract

Although autophagic pathways are essential to developmental processes, many questions still remain regarding the initiation signals that regulate autophagy in the context of differentiation. To address these questions we studied the ocular lens, as the programmed elimination of nuclei and organelles occurs in a precisely regulated spatiotemporal manner to form the organelle-free zone (OFZ), a characteristic essential for vision acuity. Here, we report our discovery that inactivation of MAPK/JNK induces autophagy for formation of the OFZ through its regulation of MTORC1, where MAPK/JNK signaling is required for both MTOR activation and RPTOR/RAPTOR phosphorylation. Autophagy pathway proteins including ULK1, BECN1/Beclin 1, and MAP1LC3B2/LC3B-II were upregulated in the presence of inhibitors to either MAPK/JNK or MTOR, inducing autophagic loss of organelles to form the OFZ. These results reveal that MAPK/JNK is a positive regulator of MTORC1 signaling and its developmentally regulated inactivation provides an inducing signal for the coordinated autophagic removal of nuclei and organelles required for lens function.

Disclosure of Potential Conflicts of Interest

No potential conflicts of interest were disclosed.

Acknowledgment

This work was supported by grant EY010577, EY14258 from the National Institutes of Health (NIH) to ASM and in part, by a grant-in-aid of research from the National Academy of Sciences, administered by Sigma Xi, The Scientific Research Society, to SB. We would like to thank Brigid Bleaken for excellent technical assistance and Iris Wolff for performing the E13 and E15 lens microdissections. We thank Janet Richards for help with the EM studies. We thank Dr Janice Walker for guiding us in the MCF-7 cell studies and for critically reading the manuscript.