Abstract
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.
Highlights
Neurons in the central nervous system (CNS) undergo limited axonal regeneration after trauma, in part because of the non-permissive environment[1,2]
A delay in the rate of motor recovery was observed in the Basso Mouse Scale (BMS) locomotion score (Fig. 1b), and impaired locomotion was observed with respect to footprints (Fig. 1c)
The major conclusion of this study is that lateral olfactory tract usher substance (LOTUS) levels are directly correlated with neural repair after spinal cord injury (SCI) and optic nerve crush
Summary
Neurons in the central nervous system (CNS) undergo limited axonal regeneration after trauma, in part because of the non-permissive environment[1,2]. AGIs are derived from glial components, such as chondroitin sulfate proteoglycan[6,7] and B lymphocyte stimulator (BLyS), which is a tumour necrosis factor superfamily member expressed in CNS astrocytes[8] Each of these five AGIs binds to Nogo receptor-1 (NgR1) and induces nerve growth cone collapse and neurite outgrowth inhibition[1,2,5,8,9,10,11]. Triple genetic deletion of Nogo, MAG, and OMgp produces greater improvement in axonal regrowth following SCI compared with a single Nogo mutation[23] These reports suggest that inhibition of the function of the multiple glial components that bind to NgR1 may improve the ability of Molecular Pharmacology and Neurobiology, Yokohama City University Graduate School of Medicine, Yokohama, 246-0004, Japan. We provide evidence showing that LOTUS plays a crucial role in neuronal regeneration following SCI
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