Selvaraj BT, Frank N, Bender FL, Asan E, Sendtner M.
Local axonal function of STAT3 rescues axon degeneration in the pmn model of motoneuron disease.
J Cell Biol. 2012 Oct 29;199(3):437-51.
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This study by Selvaraj et al. has identified an unexpected signaling pathway by which the neurotrophic factor CNTF promotes axon regeneration of motor neurons in a mouse model of motor neuron disease. In this model (progressive motor neuronopathy, or PMN mouse), a point mutation on the TBCE gene results in destabilization of tubulin-specific chaperone E, leading to defects in microtubule assembly and axon degeneration of motor neurons. Despite the fact that different neurotrophic factors, such as glial-derived neurotrophic factor (GDNF), brain-derived neurotrophic factor (BDNF), and ciliary neurotrophic factor (CNTF) can all promote survival of the cell bodies of motor neurons, this study shows that only CNTF can rescue the axon degeneration of motor neurons prepared from PMN mice. By generating conditional knockout mice that lack the transcription factor STAT3 and crossbreed with the PMN mutant mice, the authors further show that STAT3 is required for axon regeneration in response to CNTF. Surprisingly, the effect of STAT3 does not depend on its transcriptional activity. Rather, STAT3 interacts with the microtubule-destabilizing protein Stathmin in the cytoplasm after CNTF treatment, facilitating microtubule stabilization and polymerization of the PMN motor neurons. These observations strongly suggest that the transcription factor STAT3 can function outside the nucleus and acts locally to regulate microtubule assembly in the axon of motor neurons, which can have important implications in motor neuron diseases.
The study is intriguing in a number of aspects. First, it demonstrates that STAT3 is crucial in mediating the survival effect of CNTF in motor neurons, which increases our understanding of the pathology of motor neuron diseases and identifies new molecular targets for therapeutic agents. Second, it reveals that STAT3 can function in a manner independent of its transcriptional activity during axon regeneration. This contrasts with a recent study demonstrating that the retrograde transport of STAT3 into the nucleus is required for axon regeneration of dorsal root ganglion neurons after sciatic nerve injury (Ben-Yaakov et al., 2012), and suggests that STAT3 is a multifaceted signaling molecule that performs distinct functions in axon regeneration under different conditions. Third, together with recent findings from our laboratory on a critical role of STAT3 in mediating β amyloid-induced neuronal death implicated in Alzheimer’s disease (Wan et al., 2010), this study reveals that STAT3 activation can lead to survival or death of neurons in different types of neurodegenerative diseases. Finally, we previously reported that STAT3 can also be activated by ephrin (Lai et al., 2004), which negatively regulates neurotransmission in the adult brain by reducing synaptic connectivity of neurons (Fu et al., 2007; 2011). Given the localization of STAT3 at the postsynaptic density (Nicolas et al., 2012), and the demonstration in this study that STAT3 can function outside the nucleus, it would be of interest to explore whether STAT3 also acts locally at the synapse to trigger synaptic loss in neurodegenerative diseases.
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Axonal transcription factors signal retrogradely in lesioned peripheral nerve.
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Fu AK, Hung KW, Fu WY, Shen C, Chen Y, Xia J, Lai KO, Ip NY.
APC(Cdh1) mediates EphA4-dependent downregulation of AMPA receptors in homeostatic plasticity.
Nat Neurosci. 2011 Feb;14(2):181-9. Epub 2010 Dec 26
Fu WY, Chen Y, Sahin M, Zhao XS, Shi L, Bikoff JB, Lai KO, Yung WH, Fu AK, Greenberg ME, Ip NY.
Cdk5 regulates EphA4-mediated dendritic spine retraction through an ephexin1-dependent mechanism.
Nat Neurosci. 2007 Jan;10(1):67-76.
Lai KO, Chen Y, Po HM, Lok KC, Gong K, Ip NY.
Identification of the Jak/Stat proteins as novel downstream targets of EphA4 signaling in muscle: implications in the regulation of acetylcholinesterase expression.
J Biol Chem. 2004 Apr 2;279(14):13383-92.
Nicolas CS, Peineau S, Amici M, Csaba Z, Fafouri A, Javalet C, Collett VJ, Hildebrandt L, Seaton G, Choi SL, Sim SE, Bradley C, Lee K, Zhuo M, Kaang BK, Gressens P, Dournaud P, Fitzjohn SM, Bortolotto ZA, Cho K, Collingridge GL.
The Jak/STAT pathway is involved in synaptic plasticity.
Neuron. 2012 Jan 26;73(2):374-90.
Wan J, Fu AK, Ip FC, Ng HK, Hugon J, Page G, Wang JH, Lai KO, Wu Z, Ip NY.
Tyk2/STAT3 signaling mediates beta-amyloid-induced neuronal cell death: implications in Alzheimer's disease.
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