LINGO-1 Receptor Promotes Neuronal Apoptosis by Inhibiting WNK3 Kinase Activity

Zhang, Zhaohuan; Xu, Xiaohui; Xiang, Zhenghua; Yu, Zhongwang; Feng, Jifeng; He, Cheng

doi:10.1074/jbc.m112.447771

Cited by 21 publications

(10 citation statements)

References 43 publications

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“…Mi et al (2007) showed that the OPC maturation and remyelination are significantly enhanced in vitro and in vivo by inhibiting LINGO-1 function using dominant-negative LINGO-1, LINGO-1 RNAi, or LINGO-1-Fc but the specific protein that mediated the inhibition signal transduction was not described. Though our previous work has suggested that WNK1 and WNK3 are the downstream signaling molecules of LINGO-1 in neurons (Zhang et al, , 2013, little is known about their function in oligodendrocytes. In the present study, we showed that WNK1 and LINGO-1 were highly expressed in the cultured oligodendrocytes and interact with each other.…”

Section: Discussionmentioning

confidence: 99%

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WNK1 is involved in Nogo66 inhibition of OPC differentiation

Zhang

Wang

et al. 2015

Molecular and Cellular Neuroscience

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Section: Discussionmentioning

confidence: 99%

“…Cell lysates were prepared as described previously (Zhang et al, 2013) and clarified by centrifugation at 11,200 g for 20 min at 4°C. An equal amount (300-500 μl) of supernatants was incubated with 5 μl of the corresponding antibodies for 2 h at 4°C.…”

Section: Immunoprecipitation and Immunoblottingmentioning

confidence: 99%

WNK1 is involved in Nogo66 inhibition of OPC differentiation

Zhang

Wang

et al. 2015

Molecular and Cellular Neuroscience

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“…Since LINGO‐1 expression is upregulated after activation of the Trks receptors, LINGO‐1 may function in a negative feedback loop contributing to the homeostatic regulation of neurotrophin signaling. Moreover, the LINGO‐1 intracellular domain interacts with the Myt1 transcription factor 5 as well as members of serine threonine kinases including WNK1 and WNK3, which are, respectively, involved in LINGO‐1‐mediated inhibition of neurite extension 24 and neuronal apoptosis 25 …”

Section: Introductionmentioning

confidence: 99%

LINGO family receptors are differentially expressed in the mouse brain and form native multimeric complexes

et al. 2020

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Leucine‐rich repeat and immunoglobin‐domain containing (LRRIG) proteins that are commonly involved in protein‐protein interactions play important roles in nervous system development and maintenance. LINGO‐1, one of this family members, is characterized as a negative regulator of neuronal survival, axonal regeneration, and oligodendrocyte precursor cell (OPC) differentiation into mature myelinating oligodendrocytes. Three LINGO‐1 homologs named LINGO‐2, LINGO‐3, and LINGO‐4 have been described. However, their relative expression and functions remain unexplored. Here, we show by in situ hybridization and quantitative polymerase chain reaction that the transcripts of LINGO homologs are differentially expressed in the central nervous system. The immunostaining of brain slices confirmed this observation and showed the co‐expression of LINGO‐1 with its homologs. Using BRET (bioluminescence resonance energy transfer) analysis, we demonstrate that LINGO proteins can physically interact with each of the other ones with comparable affinities and thus form the oligomeric states. Furthermore, co‐immunoprecipitation experiments indicate that LINGO proteins form heterocomplexes in both heterologous systems and cortical neurons. Since LINGO‐1 is a promising target for the treatment of demyelinating diseases, its ability to form heteromeric complexes reveals a new level of complexity in its functioning and opens the way for new strategies to achieve diverse and nuanced LINGO‐1 regulation.

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“…Because LINGO-1 is implicated in potentiating neuronal apoptosis under serum-deprivation conditions, 18,[27][28][29] and the LINGO-1 receptor complex can be activated by its agonist Nogo-66 28 or by self-interaction in trans, 30 were observed when serum-deprivation cultures were treated with LINGO-1 without or with the SP1 shRNA ( Figure 2C,D). In addition, the LINGO-1 expression was found decreased after SP1 inhibition (Figure 2E).…”

Section: Regulation Of Lingo-1 Expression By Sp1 and Inhibition Of mentioning

confidence: 99%

“…12 In addition, LINGO-1 antagonists have neuroprotective effects against injury-induced apoptosis in cultured neurons. 12,17,18 We previously reported that in an optic nerve crush (ONC) model, inhibition of LINGO-1 by RNA interference promoted regeneration of the optic nerve and the survival of RGCs. 19 Although inhibition of LINGO-1 promotes the survival of neurons and RGCs, the underlying mechanism is unclear.…”

Section: Introductionmentioning

confidence: 99%

SP1‐mediated upregulation of LINGO‐1 promotes degeneration of retinal ganglion cells in optic nerve injury

Zhan

Quan

et al. 2020

CNS Neurosci Ther

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Backgrounds Insults to the axons in the optic nerve head are the primary cause of loss of retinal ganglion cells (RGCs) in traumatic, ischemic nerve injury or degenerative ocular diseases. The central nervous system–specific leucine‐rich repeat protein, LINGO‐1, negatively regulates axon regeneration and neuronal survival after injury. However, the upstream molecular mechanisms that regulate LINGO‐1 signaling and contribute to LINGO‐1–mediated death of RGCs are unclear. Methods The expression of SP1 was profiled in optic nerve crush (ONC)–injured RGCs. LINGO‐1 level was examined after SP1 overexpression by qRT‐PCR. Luciferase assay was used to examine the binding of SP1 to the promoter regions of LINGO‐1. Primary RGCs from rat retina were isolated by immunopanning and RGCs apoptosis were determined by Tunnel. SP1 and LINGO‐1 expression was investigated using immunohistochemistry and Western bolting. Neuroprotection was assessed by RGC counts, RNFL thickness, and VEP tests after inhibition of SP1 shRNA. Results We demonstrate that SP1 was upregulated in ONC‐injured RGCs. SP1 was bound to the LINGO‐1 promoter, which led to increased expression of LINGO‐1. Treatment with recombinant Nogo‐66 or LINGO‐1 promoted apoptosis of RGCs cultured under serum‐deprivation conditions, while silencing of SP1 promoted the survival of RGCs. SP1 and LINGO‐1 colocalized and were upregulated in ONC‐injured retinas. Silencing of SP1 in vivo reduced LINGO‐1 expression and protected the structure of RGCs from ONC‐induced injury, but there was no sign of recovery in VEP. Conclusions Our findings imply that SP1 regulates LINGO‐1 expression in RGCs in the injured retina and provide insight into mechanisms underlying LINGO‐1–mediated RGC death in optic nerve injury.

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LINGO-1 Receptor Promotes Neuronal Apoptosis by Inhibiting WNK3 Kinase Activity

Cited by 21 publications

References 43 publications

WNK1 is involved in Nogo66 inhibition of OPC differentiation

WNK1 is involved in Nogo66 inhibition of OPC differentiation

LINGO family receptors are differentially expressed in the mouse brain and form native multimeric complexes

SP1‐mediated upregulation of LINGO‐1 promotes degeneration of retinal ganglion cells in optic nerve injury

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