Interaction of neurotrophin signaling with Bcl-2 localized to the mitochondria and endoplasmic reticulum on spiral ganglion neuron survival and neurite growth

John P Renton; Ningyong Xu; J Jason Clark; Marlan R Hansen

doi:10.1002/jnr.22381

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Interaction of neurotrophin signaling with Bcl-2 localized to the mitochondria and endoplasmic reticulum on spiral ganglion neuron survival and neurite growth

Journal article

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Peer reviewed

Interaction of neurotrophin signaling with Bcl-2 localized to the mitochondria and endoplasmic reticulum on spiral ganglion neuron survival and neurite growth

John P Renton, Ningyong Xu, J Jason Clark and Marlan R Hansen

Journal of neuroscience research, Vol.88(10), pp.2239-2251

08/01/2010

DOI: 10.1002/jnr.22381

PMCID: PMC3292436

PMID: 20209634

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Abstract

Enhanced spiral ganglion neuron (SGN) survival and regeneration of peripheral axons following deafness will likely enhance the efficacy of cochlear implants. Overexpression of Bcl-2 prevents SGN death but inhibits neurite growth. Here we assessed the consequences of Bcl-2 targeted to either the mitochondria (GFP-Bcl-2-Maob) or the endoplasmic reticulum (ER, GFP-Bcl-2-Cb5) on cultured SGN survival and neurite growth. Transfection of wild-type GFP-Bcl-2, GFP-Bcl-2-Cb5, or GFP-Bcl-2-Maob increased SGN survival, with GFP-Bcl-2-Cb5 providing the most robust response. Paradoxically, expression of GFP-Bcl-2-Maob results in SGN death in the presence of neurotrophin-3 (NT-3) and brain-derived neurotrophic factor (BDNF), neurotrophins that independently promote SGN survival via Trk receptors. This loss of SGNs is associated with cleavage of caspase 3 and appears to be specific for neurotrophin signaling, insofar as coexpression of constitutively active mitogen-activated kinase kinase (MEKDeltaEE) or phosphatidyl inositol-3 kinase (P110), but not other prosurvival stimuli (e.g., membrane depolarization), also results in the loss of SGNs expressing GFP-Bcl-2-Maob. MEKDeltaEE and P110 promote SGN survival, whereas P110 promotes neurite growth to a greater extent than NT-3 or MEKDeltaEE. However, wild-type GFP-Bcl-2, GFP-Bcl-2-Cb5, and GFP-Bcl-2-Maob inhibit neurite growth even in the presence of neurotrophins, MEKDeltaEE, or P110. Historically, Bcl-2 has been thought to act primarily at the mitochondria to prevent neuronal apoptosis. Nevertheless, our data show that Bcl-2 targeted to the ER is more effective at rescuing SGNs in the absence of trophic factors. Additionally, Bcl-2 targeted to the mitochondria results in SGN death in the presence of neurotrophins. (c) 2010 Wiley-Liss, Inc.

Signal Transduction

Neurites - physiology

Spiral Ganglion - physiology

Cells, Cultured

Endoplasmic Reticulum - metabolism

Rats

Mitochondria - metabolism

Nerve Growth Factors - metabolism

Cell Enlargement

Proto-Oncogene Proteins c-bcl-2 - metabolism

Animals

Cell Death - physiology

Neurotrophin 3 - metabolism

Neurons - physiology

Brain-Derived Neurotrophic Factor - metabolism

Proto-Oncogene Proteins c-bcl-2 - genetics

Cell Survival - physiology

Details

Title: Subtitle: Interaction of neurotrophin signaling with Bcl-2 localized to the mitochondria and endoplasmic reticulum on spiral ganglion neuron survival and neurite growth
Creators: John P Renton - Department of Otolaryngology-Head and Neck Surgery, University of Iowa, Iowa City, Iowa
Ningyong Xu
J Jason Clark
Marlan R Hansen
Resource Type: Journal article
Publication Details: Journal of neuroscience research, Vol.88(10), pp.2239-2251
Publisher: United States
DOI: 10.1002/jnr.22381
PMID: 20209634
PMCID: PMC3292436
ISSN: 0360-4012
eISSN: 1097-4547
Grant note: P50 DC000242-24 / NIDCD NIH HHS P50 DC000242 / NIDCD NIH HHS K08 DC006211 / NIDCD NIH HHS
Language: English
Date published: 08/01/2010
Academic Unit: Molecular Physiology and Biophysics; Neurosurgery; Otolaryngology
Record Identifier: 9984007178002771

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