Enhanced Transcriptional Activity and Mitochondrial Localization of STAT3 Co-induce Axon Regrowth in the Adult Central Nervous System

Publication date: Available online 31 March 2016
Source:Cell Reports
Author(s): Xueting Luo, Marcio Ribeiro, Eric R. Bray, Do-Hun Lee, Benjamin J. Yungher, Saloni T. Mehta, Kinjal A. Thakor, Francisca Diaz, Jae K. Lee, Carlos T. Moraes, John L. Bixby, Vance P. Lemmon, Kevin K. Park
Signal transducer and activator of transcription 3 (STAT3) is a transcription factor central to axon regrowth with an enigmatic ability to act in different subcellular regions independently of its transcriptional roles. However, its roles in mature CNS neurons remain unclear. Here, we show that along with nuclear translocation, STAT3 translocates to mitochondria in mature CNS neurons upon cytokine stimulation. Loss- and gain-of-function studies using knockout mice and viral expression of various STAT3 mutants demonstrate that STAT3′s transcriptional function is indispensable for CNS axon regrowth, whereas mitochondrial STAT3 enhances bioenergetics and further potentiates regrowth. STAT3′s localization, functions, and growth-promoting effects are regulated by mitogen-activated protein kinase kinase (MEK), an effect further enhanced by Pten deletion, leading to extensive axon regrowth in the mouse optic pathway and spinal cord. These results highlight CNS neuronal dependence on STAT3 transcriptional activity, with mitochondrial STAT3 providing ancillary roles, and illustrate a critical contribution for MEK in enhancing diverse STAT3 functions and axon regrowth.

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Teaser

Luo et al. provide mechanistic insights into how STAT3 induces axon regeneration and sprouting after injury. They demonstrate that exploiting STAT3′s effects in combination with modulation of MEK and PTEN promotes extensive CNS axon regrowth.


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