The carboxyl-terminal region of Crtac1B/LOTUS acts as a functional domain in endogenous antagonism to Nogo receptor-1

Kikuchi, Yuji; Arie, Yuko; Iketani, Masumi; Ito, Hiromu; Nishiyama, Kuniyuki; Sato, Yasufumi; Nakamura, Fumio; Mizuki, Nobuhisa; Goshima, Yoshio; Takei, Kohtaro

doi:10.1016/j.bbrc.2012.01.033

Cited by 21 publications

(15 citation statements)

References 26 publications

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“…Inactivation of cofilin by LIM kinase stabilizes the actin filament in the growth cone, resulting in the inhibition of neurite outgrowth. Recently, cartilage acidic protein-1b (lotus) was identified as a protein that endogenously antagonizes NgR1 (Sato et al, 2011 ; Kurihara et al, 2012 ). Lotus suppresses Nogo-NgR1 binding and Nogo-induced growth cone collapse.…”

Section: Rhoa/rock Signaling and Axon Growth Inhibitionmentioning

confidence: 99%

Axon growth inhibition by RhoA/ROCK in the central nervous system

2014

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Rho kinase (ROCK) is a serine/threonine kinase and a downstream target of the small GTPase Rho. The RhoA/ROCK pathway is associated with various neuronal functions such as migration, dendrite development, and axonal extension. Evidence from animal studies reveals that RhoA/ROCK signaling is involved in various central nervous system (CNS) diseases, including optic nerve and spinal cord injuries, stroke, and neurodegenerative diseases. Given that RhoA/ROCK plays a critical role in the pathophysiology of CNS diseases, the development of therapeutic agents targeting this pathway is expected to contribute to the treatment of CNS diseases. The RhoA/ROCK pathway mediates the effects of myelin-associated axon growth inhibitors—Nogo, myelin-associated glycoprotein (MAG), oligodendrocyte-myelin glycoprotein (OMgp), and repulsive guidance molecule (RGM). Blocking RhoA/ROCK signaling can reverse the inhibitory effects of these molecules on axon outgrowth, and promotes axonal sprouting and functional recovery in animal models of CNS injury. To date, several RhoA/ROCK inhibitors have been under development or in clinical trials as therapeutic agents for neurological disorders. In this review, we focus on the RhoA/ROCK signaling pathway in neurological disorders. We also discuss the potential therapeutic approaches of RhoA/ROCK inhibitors for various neurological disorders.

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Section: Rhoa/rock Signaling and Axon Growth Inhibitionmentioning

confidence: 99%

Axon growth inhibition by RhoA/ROCK in the central nervous system

2014

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“…Searching for molecules that could affect the development of the lateral olfactory tract it was found that Lateral Olfactory Tract Usher Substance (LOTUS) could inhibit the binding of Nogo-A to NgR1. Thereby local Nogo-NgR1 growth inhibition can be blocked (Sato et al, 2011), as mediated through the C-terminal domain of LOTUS (Kurihara et al, 2012).…”

Section: Endogenous Ngr1 Inhibitorsmentioning

confidence: 99%

Neuronal Overexpression of Nogo Receptor 1 in APPswe/PSEN1(ΔE9) Mice Impairs Spatial Cognition Tasks without Influencing Plaque Formation

Karlsson

Karlén

Olson

et al. 2012

JAD

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In the search for molecules that may alter the formation of amyloid-β (Aβ) protofibrils, it has been shown that the Nogo-system can interact and bind to amyloid-β protein precursor and thus affect the amount of Aβ that is formed and deposited in the brain. To further address this issue in vivo, we crossed mice that overexpress Nogo receptor 1 (NgR1), "MemoFlex", in forebrain neurons, with plaque forming APPswe/PSEN1(ΔE9) mice, to investigate if increased levels of NgR1 would influence plaque load or cognitive function in the resulting MemoFlex/APPswe/PSEN1(ΔE9) transgenic mice. We used a radial arm water maze and the Morris water maze to measure cognitive function. We did not find any significant effect of NgR1 overexpression on the performance of APPswe/PSEN1(ΔE9) mice in the radial arm water maze test. However, MemoFlex/APPswe/PSEN1(ΔE9) mice were found to be significantly impaired in the Morris water maze. We also analyzed the amount of plaques in the two mouse models without finding any significant difference in plaque load in the cerebral cortex or the hippocampal formation. It therefore appears that overexpression of NgR1 in APPswe/PSEN1(ΔE9) mice does not have any marked effects on Aβ levels, yet appears to impair spatial cognitive abilities. We conclude that strong overexpression of NgR1 in forebrain neurons impairs aspects of cognitive function but does not markedly alter plaque load in plaque-forming APPswe/PSEN1(ΔE9) mice. Thus high levels of membrane-bound NgR1 present since early postnatal life does not influence the development of plaques in mice carrying the two human plaque-causing mutations APPswe and PSEN1(ΔE9).

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“…Recently, an endogenous NgR1 antagonist, lateral olfactory tract usher substance (LOTUS)/cartilage acidic protein-1B (Crtac1B) was identified in the developing brain and shown to contribute to axon tract formation by antagonizing Nogo-induced NgR1 function 24 . The carboxyl-terminal region of LOTUS binds to NgR1 25 and blocks the binding of four AGIs (Nogo, MAG, OMgp, BLyS) to NgR1 as well as their axonal growth inhibition 26 . Therefore, LOTUS is a potent endogenous inhibitor of NgR1 function.…”

Section: Introductionmentioning

confidence: 99%

Regulation of axonal regeneration by the level of function of the endogenous Nogo receptor antagonist LOTUS

Hirokawa

Zou

Kikuchi

et al. 2017

Sci Rep

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Axonal regeneration in the adult mammalian central nervous system is limited in part by the non-permissive environment, including axonal growth inhibitors such as the Nogo-A protein. How the functions of these inhibitors can be blocked remains unclear. Here, we examined the role of LOTUS, an endogenous Nogo receptor antagonist, in promoting functional recovery and neural repair after spinal cord injury (SCI), as well as axonal regeneration after optic nerve crush. Wild-type untreated mice show incomplete but substantial intrinsic motor recovery after SCI. The genetic deletion of LOTUS delays and decreases the extent of motor recovery, suggesting that LOTUS is required for spontaneous neural repair. The neuronal overexpression of LOTUS in transgenic mice promotes motor recovery after SCI, and recombinant viral overexpression of LOTUS enhances retinal ganglion cell axonal regeneration after optic nerve crush. Thus, the level of LOTUS function titrates axonal regeneration.

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The carboxyl-terminal region of Crtac1B/LOTUS acts as a functional domain in endogenous antagonism to Nogo receptor-1

Cited by 21 publications

References 26 publications

Axon growth inhibition by RhoA/ROCK in the central nervous system

Axon growth inhibition by RhoA/ROCK in the central nervous system

Neuronal Overexpression of Nogo Receptor 1 in APPswe/PSEN1(ΔE9) Mice Impairs Spatial Cognition Tasks without Influencing Plaque Formation

Regulation of axonal regeneration by the level of function of the endogenous Nogo receptor antagonist LOTUS

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