Axonal branching in lateral olfactory tract is promoted by Nogo signaling

Abstract

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.

Selective CNS Targeting and Distribution with a Refined Region-Specific Intranasal Delivery Technique via the Olfactory Mucosa

“…To explore the transport path from the olfactory region to the brain and to study kinetics of distribution and elimination, study 3 was designed with two different murine IgG antibodies and a scFv. The IgG1 antibody 11C7 binds to Nogo-A, which is predominantly expressed within the CNS but some reports have detected it in OSN [31,32]. The 11C7 was used as it is a promising antibody for multiple sclerosis or similar neurodegenerative diseases as it was shown that 11C7 therapy induces neuronal outgrowth in studies performed by Schwab and coworkers [33][34][35][36][37].…”

Glial Cell-Axonal Growth Cone Interactions in Neurodevelopment and Regeneration

“…It is important to note that the developmental time point when myelin becomes abundant is much later than the appearance of nascent axon growth cones; thus, it is unlikely that MAIs play a major role in shaping neuronal networks (McKerracher and Rosen, 2015). Nonetheless, there are numerous studies examining the impact of several inhibitory molecules, especially the semaphorins, on various neurodevelopmental events (Iketani et al, 2016;Wang L. et al, 2017), but these are outside the scope of this review.…”

Augmented Expression of NOGO-A and Its Receptors in Human Retinal Pigment Epithelial Cells Following Treatment with Human Amniotic Fluid

“…High sensitivity to the inhibitory effects of Nogo-A was detected in RGC axons (37,38). Nogo-A is highly upregulated in RGC axons, when the axons maturate and elongate in the presumptive optic nerve towards the brain (39), that is associated with collateral branches development (16,40). We observed that NOGO-A was strongly elevated in hRPE cells in HAF culture.…”

“…As HAF has shown neural transdifferentiation effect on hRPE cells (30,31), the elevated expression of NOGO-A in the treated cells can be explained as the regulatory role of Nogo-A and its receptors in neurite branching and extension that occur in the development of nervous system. Nogo receptor (NgR) has inhibitory effects on neuronal axon growth (21,40). NgR can interact with integrins, to decrease integrin activity and cell-substrate adhesion and a transactivation of the epidermal growth factor (EGF) receptor involving in cell migration and growth (41,42).…”