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- Title
The Soluble Form of LOTUS inhibits Nogo Receptor-Mediated Signaling by Interfering with the Interaction Between Nogo Receptor Type 1 and p75 Neurotrophin Receptor.
- Authors
Yutaka Kawakami; Yuji Kurihara; Yu Saito; Yuki Fujita; Toshihide Yamashita; Kohtaro Takei
- Abstract
Nogo receptor type 1 (NgRl) is known to inhibit neuronal regeneration in the CNS. Previously, we have shown that lateral olfactory tract usher substance (LOTUS) interacts with NgRl 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 NgRl function as a candidate for therapeutic agents. Here, we show that s-LOTUS inhibits NgRl-mediated signaling by inhibiting the molecular interaction between NgRl and its coreceptor, p75 neurotrophin receptor (p75 NTR). In contrast to the membrane-bound form of LOTUS, s-LOTUS did not block ligand binding to NgRl. However, we identified p75NTR as a novel LOTUS binding partner and found that s-LOTUS suppressed the interaction between p75 NTR and NgRl. s-LOTUS inhibited myelinassociated 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, whereas olfactory bulb neurons of lotus-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 NgRl-mediated signaling, possibly by interfering with the interaction between NgRl and p75NTR. Therefore, s-LOTUS may have potential as a therapeutic agent for neuronal regeneration in the damaged CNS.
- Subjects
NOGO receptors; NEUROTROPHIN receptors; OLFACTORY receptors; LIGAND binding (Biochemistry); NEUROSCIENCES
- Publication
Journal of Neuroscience, 2018, Vol 38, Issue 10, p2589
- ISSN
0270-6474
- Publication type
Article
- DOI
10.1523/JNEUROSCI.0953-17.2018