<i>PIKE</i>is essential for oligodendroglia development and CNS myelination

Chan, Chi Bun; Liu, Xia; Zhao, Lixia; Liu, Guanglu; Lee, Chi Wai; Feng, Yue; Ye, Keiqang

doi:10.1073/pnas.1318185111

Cited by 14 publications

(12 citation statements)

References 46 publications

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“…PIKE is a GTPase (Ye and Snyder, 2004) that connects extracellular signals (netrin, glutamate, and neurotrophins) to the intracellular PI3K/AKT signaling cascade (Chan et al, 2012; Hu et al, 2005; Liu et al, 2008). Conditional knockout of PIKE in PLP+ OLs resulted in impaired OPC proliferation along with decreased differentiation and remyelination (Chan et al, 2014). These results suggest that the AKT pathway plays an important role during remyelination by ensuring the adequate generation of OPCs and the appropriate differentiation of OLs.…”

Section: Akt/mtor Signaling Pathwaymentioning

confidence: 99%

Intracellular signaling pathway regulation of myelination and remyelination in the CNS

Gaesser

Fyffe-Maricich

2016

Experimental Neurology

173

139

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The restoration of myelin sheaths on demyelinated axons remains a major obstacle in the treatment of multiple sclerosis (MS). Currently approved therapies work by modulating the immune system to reduce the number and rate of lesion formation but are only partially effective since they are not able to restore lost myelin. In the healthy CNS, myelin continues to be generated throughout life and spontaneous remyelination occurs readily in response to insults. In patients with MS, however, remyelination eventually fails, at least in part as a result of a failure of oligodendrocyte precursor cell (OPC) differentiation and the subsequent production of new myelin. A better understanding of the molecular mechanisms and signaling pathways that drive the process of myelin sheath formation is therefore important in order to speed the development of novel therapeutics designed to target remyelination. Here we review data supporting critical roles for three highly conserved intracellular signaling pathways: Wnt/β-catenin, PI3K/AKT/mTOR, and ERK/MAPK in the regulation of OPC differentiation and myelination both during development and in remyelination. Potential points of crosstalk between the three pathways and important areas for future research are also discussed.

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Section: Akt/mtor Signaling Pathwaymentioning

confidence: 99%

Intracellular signaling pathway regulation of myelination and remyelination in the CNS

Gaesser

Fyffe-Maricich

2016

Experimental Neurology

173

139

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“…We used the following primary antibodies in this study: monoclonal antibodies specific for cyclin D3 (MBL, Nagoya, Japan), S-100ß (Sigma-Aldrich, St. Louis, MO), calbindin D28k (Swant Swiss antibodies, Switzerland), PKCalpha (Sigma-Aldrich, St. Louis, MO), Pax6 (Developmental Studies Hybridoma Bank, Iowa City, IA), HPC-1 (Sigma-Aldrich, St. Louis, MO), Brn3a (Merck Millipore, Billerica, MA), Ki-67 (BD Pharmingen, San Diego, CA), QKI-6 and QKI-7 (NeuroMab, Davis, CA) [ 23 ]. We used a rabbit polyclonal antibody against pan QKI (HPA019123, Atlas antibodies, Stockholm, Sweden) and QKI-5 (A300-183A, Bethyl laboratories, Montgomery, TX) [ 23 ]; and a sheep polyclonal antibody against Chx10 (Exalpha Biologicals Inc., Shirley, MA). Alexa secondary antibodies (Molecular Probes, Eugene, OR) were used at a concentration of 1:500; and TO-PRO-3 (Molecular Probes, Eugene, OR), at a concentration of 1:1000.…”

Section: Methodsmentioning

confidence: 99%

“…The protein concentrations of each sample were estimated from the intensity profile of total proteins on SDS-PAGE by coomassie staining. For detection, we used the polyclonal anti-QKI-5 antibody from Bethyl laboratories (Montgomery, TX) and monoclonal anti-QKI-6 and QKI-7 antibodies from NeuroMab (UC Davis, CA, USA)[ 23 ].…”

Section: Methodsmentioning

confidence: 99%

Expression of Quaking RNA-Binding Protein in the Adult and Developing Mouse Retina

et al. 2016

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Quaking (QKI), which belongs to the STAR family of KH domain-containing RNA-binding proteins, functions in pre-mRNA splicing, microRNA regulation, and formation of circular RNA. QKI plays critical roles in myelinogenesis in the central and peripheral nervous systems and has been implicated neuron-glia fate decision in the brain; however, neither the expression nor function of QKI in the neural retina is known. Here we report the expression of QKI RNA-binding protein in the developing and mature mouse retina. QKI was strongly expressed by Müller glial cells in both the developing and adult retina. Intriguingly, during development, QKI was expressed in early differentiating neurons, such as the horizontal and amacrine cells, and subsequently in later differentiating bipolar cells, but not in photoreceptors. Neuronal expression was uniformly weak in the adult. Among QKI isoforms (5, 6, and 7), QKI-5 was the predominantly expressed isoform in the adult retina. To study the function of QKI in the mouse retina, we examined quakingviable(qkv) mice, which have a dysmyelination phenotype that results from deficiency of QKI expression and reduced numbers of mature oligodendrocytes. In homozygous qkv mutant mice (qkv/qkv), the optic nerve expression levels of QKI-6 and 7, but not QKI-5 were reduced. In the retina of the mutant homozygote, QKI-5 levels were unchanged, and QKI-6 and 7 levels, already low, were also unaffected. We conclude that QKI is expressed in developing and adult Müller glia. QKI is additionally expressed in progenitors and in differentiating neurons during retinal development, but expression weakened or diminished during maturation. Among QKI isoforms, we found that QKI-5 predominated in the adult mouse retina. Since Müller glial cells are thought to share properties with retinal progenitor cells, our data suggest that QKI may contribute to maintaining retinal progenitors prior to differentiation into neurons. On the other hand, the expression of QKI in different retinal neurons may suggest a role in neuronal cell type specific fate determination and maturation. The data raises the possibility that QKI may function in retinal cell fate determination and maturation in both glia and neurons.

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“…The BDNF-mediated PI3K/Akt pathway, but not the MAPK pathway, is selectively diminished when PIKE is depleted. Consequently, PIKE −/− neurons are more vulnerable to glutamate-or stroke-induced cell death (24)(25)(26). Most recently, we demonstrated that PIKE-A, an isoform in the PIKE family, binds the AMPK α subunit and suppresses its activation and kinase activity, and this interaction is enhanced by Fyn phosphorylation of PIKE-A (27).…”

Section: Significancementioning

confidence: 99%

α-Synuclein binds and sequesters PIKE-L into Lewy bodies, triggering dopaminergic cell death via AMPK hyperactivation

Kang

Zhang

Liu

et al. 2017

Proc. Natl. Acad. Sci. U.S.A.

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The abnormal aggregation of fibrillar α-synuclein in Lewy bodies plays a critical role in the pathogenesis of Parkinson's disease. However, the molecular mechanisms regulating α-synuclein pathological effects are incompletely understood. Here we show that α-synuclein binds phosphoinositide-3 kinase enhancer L (PIKE-L) in a phosphorylationdependent manner and sequesters it in Lewy bodies, leading to dopaminergic cell death via AMP-activated protein kinase (AMPK) hyperactivation. α-Synuclein interacts with PIKE-L, an AMPK inhibitory binding partner, and this action is increased by S129 phosphorylation through AMPK and is decreased by Y125 phosphorylation via Src family kinase Fyn. A pleckstrin homology (PH) domain in PIKE-L directly binds α-synuclein and antagonizes its aggregation. Accordingly, PIKE-L overexpression decreases dopaminergic cell death elicited by 1-methyl-4-phenylpyridinium (MPP + ), whereas PIKE-L knockdown elevates α-synuclein oligomerization and cell death. The overexpression of 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) or α-synuclein induces greater dopaminergic cell loss and more severe motor defects in PIKE-KO and Fyn-KO mice than in wild-type mice, and these effects are attenuated by the expression of dominant-negative AMPK. Hence, our findings demonstrate that α-synuclein neutralizes PIKE-L's neuroprotective actions in synucleinopathies, triggering dopaminergic neuronal death by hyperactivating AMPK.neurodegenerative disease | dopamine | Lewy bodies

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PIKEis essential for oligodendroglia development and CNS myelination

Cited by 14 publications

References 46 publications

Intracellular signaling pathway regulation of myelination and remyelination in the CNS

Intracellular signaling pathway regulation of myelination and remyelination in the CNS

Expression of Quaking RNA-Binding Protein in the Adult and Developing Mouse Retina

α-Synuclein binds and sequesters PIKE-L into Lewy bodies, triggering dopaminergic cell death via AMPK hyperactivation

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