LOTUS suppresses axon growth inhibition by blocking interaction between Nogo receptor-1 and all four types of its ligand

Kikuchi, Yuji; Iketani, Masumi; Ito, Hiromu; Nishiyama, Kuniyuki; Sakakibara, Yusuke; Goshima, Yoshio; Takei, Kohtaro

doi:10.1016/j.mcn.2014.07.001

Cited by 30 publications

(46 citation statements)

References 34 publications

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“…We have previously reported that LOTUS antagonizes NgR1 signaling915. Therefore, we predicted that NgR1 function is induced by an increase of Nogo-A and that a decrease in LOTUS may be involved in axonal collateral branching of the LOT.…”

Section: Resultsmentioning

confidence: 91%

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Axonal branching in lateral olfactory tract is promoted by Nogo signaling

Iketani

Yokoyama

Kikuchi

et al. 2016

Sci Rep

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Mitral cells are major projection neurons of the olfactory bulb (OB) that form an axonal bundle known as the lateral olfactory tract (LOT). After axonal bundle formation, collateral branches sprout from primary axons of the LOT. Recently, we identified LOT usher substance (LOTUS) as an endogenous Nogo receptor-1 (NgR1) antagonist and demonstrated that LOTUS contributes to the formation of the LOT axonal bundle. Immunoblots revealed that the expression level of Nogo-A in the OB developmentally increased during axonal collateral formation. Next, we found that the axonal collateral branches were increased in cultured OB neurons from LOTUS-knockout (KO) mice, whereas they were decreased in cultured OB neurons from NgR1-KO mice. Knockdown of Nogo-A in cultured OB neurons reduced the number of axonal collateral branches, suggesting that endogenous Nogo-A induces axonal branching. Finally, the collateral branches of the LOT were increased in LOTUS-KO mice, whereas those in NgR1-KO mice were decreased. Moreover, the abnormal increase of axonal branching observed in LOTUS-KO mice was rescued in the double mutant of LOTUS- and NgR1-KO mice. These findings suggest that Nogo-A and NgR1 interactions may contribute to axonal branching in LOT development.

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Section: Resultsmentioning

confidence: 91%

“…We recently discovered that LOTUS not only inhibited the signaling of Nogo but also MAG, OMgp and BLyS through blocking the interactions between these ligands and NgR115. However, the physiological roles of Nogo and NgR1 are not well known in the developing brain.…”

mentioning

confidence: 99%

Axonal branching in lateral olfactory tract is promoted by Nogo signaling

Iketani

Yokoyama

Kikuchi

et al. 2016

Sci Rep

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“…Several molecules expressed in neurons and glial cells trigger the intracellular signaling that gives raise to the failure to regenerate (Niclou et al, 2006;Yiu and He, 2006;Schwab, 2010). NgR1 is known to be one of the main inhibitory factors of neuronal regeneration and a common receptor of MAIs [Nogo-A (GrandPré et al, 2000;Fournier et al, 2001), myelin-associated glycoprotein (MAG) , and oligodendrocyte my-elin glycoprotein (OMgp) (Wang et al, 2002b)], B lymphocyte stimulator (BLyS) (Zhang et al, 2009), and chondroitin sulfate proteoglycans (CSPGs) (Dickendesher et al, 2012). The binding of these molecules to NgR1 is the start point of the signaling and the interaction of NgR1 with its coreceptors p75 NTR and leucinerich repeat and Ig domain-containing Nogo receptor-interacting protein 1 (LINGO-1) is essential for signal transduction due to the lack of an intracellular domain of NgR1 (Wang et al, 2002a;Mi et al, 2004).…”

Section: Introductionmentioning

confidence: 99%

“…The binding of these molecules to NgR1 is the start point of the signaling and the interaction of NgR1 with its coreceptors p75 NTR and leucinerich repeat and Ig domain-containing Nogo receptor-interacting protein 1 (LINGO-1) is essential for signal transduction due to the lack of an intracellular domain of NgR1 (Wang et al, 2002a;Mi et al, 2004). Signal transduction via this complex results in growth cone collapse and neurite outgrowth inhibition through activation of the small GTPase Rho (Fournier et al, 2003;Mi et al, 2004;Yiu and He, 2006). Many studies have demonstrated that counteracting Nogo-A (Bregman et al, 1995), NgR1 (GrandPré et al, 2002;Fischer et al, 2004), and RhoA activation (Fournier et al, 2003;Yamashita and Tohyama, 2003) promotes neuronal regeneration.…”

Section: Introductionmentioning

confidence: 99%

“…Signal transduction via this complex results in growth cone collapse and neurite outgrowth inhibition through activation of the small GTPase Rho (Fournier et al, 2003;Mi et al, 2004;Yiu and He, 2006). Many studies have demonstrated that counteracting Nogo-A (Bregman et al, 1995), NgR1 (GrandPré et al, 2002;Fischer et al, 2004), and RhoA activation (Fournier et al, 2003;Yamashita and Tohyama, 2003) promotes neuronal regeneration. Therefore, NgR1-mediated signaling is expected to be a therapeutic target for neuronal regeneration in the damaged CNS.…”

Section: Introductionmentioning

confidence: 99%

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The Soluble Form of LOTUS inhibits Nogo Receptor-Mediated Signaling by Interfering with the Interaction Between Nogo Receptor Type 1 and p75 Neurotrophin Receptor

et al. 2018

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Nogo receptor type 1 (NgR1) is known to inhibit neuronal regeneration in the CNS. We have previously identified lateral olfactory tract usher substance (LOTUS) interacts with NgR1 and inhibits its function by blocking its ligand binding. Therefore, LOTUS is expected to have therapeutic potential for the promotion of neuronal regeneration. However, it remains unknown whether the soluble form of LOTUS (s-LOTUS) also has an inhibitory action on NgR1 function as a candidate for therapeutic agents. Here, we show that s-LOTUS inhibits NgR1-mediated signaling by inhibiting the molecular interaction between NgR1 and its co-receptor p75 neurotrophin receptor (p75). In contrast to the membrane-bound form of LOTUS, s-LOTUS did not block ligand binding to NgR1. However, we identified p75 as a novel LOTUS binding partner, and found that s-LOTUS suppressed the interaction between p75 and NgR1. s-LOTUS inhibited myelin-associated inhibitor (MAI)-induced RhoA activation in murine cortical neurons. Functional analyses revealed that s-LOTUS inhibited MAI-induced growth cone collapse and neurite outgrowth inhibition in chick DRG neurons. In addition, while olfactory bulb (OB) neurons of -KO mice are sensitive to MAI due to a lack of LOTUS expression, treatment with s-LOTUS inhibited MAI-induced growth cone collapse in these neurons. Finally, we observed that s-LOTUS promoted axonal regeneration in optic nerve crush injury of mice (either sex). These findings suggest that s-LOTUS inhibits NgR1-mediated signaling possibly by interfering with the interaction between NgR1 and p75 Thus, s-LOTUS may have potential as a therapeutic agent for neuronal regeneration in the damaged CNS.Nogo receptor type 1 (NgR1) is a well-known receptor to inhibit neuronal regeneration in the CNS. Because the membrane-bound form of LOTUS antagonizes NgR1 through a cis-type molecular interaction between LOTUS and NgR1, the soluble form of LOTUS (s-LOTUS) is expected to be a therapeutic agent for neuronal regeneration. In our present study, we show that s-LOTUS inhibits the interaction between NgR1 and p75, NgR1 ligand-induced RhoA activation, growth cone collapse and neurite outgrowth inhibition, and promotes axonal regeneration. Our results indicate that s-LOTUS inhibits NgR1-mediated signaling through a trans-type molecular interaction between LOTUS and NgR1, and therefore, s-LOTUS may have therapeutic potential for neuronal regeneration.

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The Regulatory Role of Reticulons in Neurodegeneration: Insights Underpinning Therapeutic Potential for Neurodegenerative Diseases

Pradhan

Das

2020

Cell Mol Neurobiol

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LOTUS suppresses axon growth inhibition by blocking interaction between Nogo receptor-1 and all four types of its ligand

Cited by 30 publications

References 34 publications

Axonal branching in lateral olfactory tract is promoted by Nogo signaling

Axonal branching in lateral olfactory tract is promoted by Nogo signaling

The Soluble Form of LOTUS inhibits Nogo Receptor-Mediated Signaling by Interfering with the Interaction Between Nogo Receptor Type 1 and p75 Neurotrophin Receptor

The Regulatory Role of Reticulons in Neurodegeneration: Insights Underpinning Therapeutic Potential for Neurodegenerative Diseases

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