Cell type-specific Nogo-A gene ablation promotes axonal regeneration in the injured adult optic nerve

Abstract

Nogo-A is a well-known myelin-enriched inhibitory protein for axonal growth and regeneration in the central nervous system (CNS). Besides oligodendrocytes, our previous data revealed that Nogo-A is also expressed in subpopulations of neurons including retinal ganglion cells, in which it can have a positive role in the neuronal growth response after injury, through an unclear mechanism. In the present study, we analyzed the opposite roles of glial versus neuronal Nogo-A in the injured visual system. To this aim, we created oligodendrocyte (Cnp-Cre þ / À xRtn4/Nogo-A flox/flox ) and neuron-specific (Thy1-Cre tg þ xRtn4 flox/flox ) conditional Nogo-A knock-out (KO) mouse lines. Following complete intraorbital optic nerve crush, both spontaneous and inflammation-mediated axonal outgrowth was increased in the optic nerves of the glia-specific Nogo-A KO mice. In contrast, neuron-specific deletion of Nogo-A in a KO mouse line or after acute gene recombination in retinal ganglion cells mediated by adeno-associated virus serotype 2.Cre virus injection in Rtn4 flox/flox animals decreased axon sprouting in the injured optic nerve. These results therefore show that selective ablation of Nogo-A in oligodendrocytes and myelin in the optic nerve is more effective at enhancing regrowth of injured axons than what has previously been observed in conventional, complete Nogo-A KO mice. Our data also suggest that neuronal Nogo-A in retinal ganglion cells could participate in enhancing axonal sprouting, possibly by cis-interaction with Nogo receptors at the cell membrane that may counteract trans-Nogo-A signaling. We propose that inactivating Nogo-A in glia while preserving neuronal Nogo-A expression may be a successful strategy to promote axonal regeneration in the CNS.

Nogo‐A inhibits vascular regeneration in ischemic retinopathy

“…We have previously reported that glia-specific inactivation of Nogo-A increased retinal ganglion cell plasticity after optic nerve injury (Vajda et al, 2015) and after monocular deprivation in intact animals (Guzik-Kornacka et al, 2016). In the brain, the Nogo-A-S1PR2 ligandreceptor pair may also operate in the mechanisms controlling blood vessel plasticity after stroke.…”

Can mammalian vision be restored following optic nerve degeneration?

“…15 Severed RGC axons, such as the spinal cord long tracts, have no capacity to regenerate under normal physiological circumstances. This is due to the virtually ubiquitous presence of factors that inhibit axon regeneration, such as Nogo, chondroitin sulfate proteoglycan (CSPG), and myelinassociated glycoprotein (MAG).…”

“…This is due to the virtually ubiquitous presence of factors that inhibit axon regeneration, such as Nogo, chondroitin sulfate proteoglycan (CSPG), and myelinassociated glycoprotein (MAG). 15 Similarly, although axons of embryonic RGCs can grow axons into the superior colliculus, RGC axons of postnatal animals fail to extend into CNS tissue, even when it is derived from the embryonic tectum. 16 Thus, the failure to reestablish vision is a multifactorial phenomenon:…”

New Insights into the Roles of Nogo-A in CNS Biology and Diseases

“…Both MLC II and cofilin can also be regulated through the RhoA/ROCK pathway and respectively result in actomyosin contraction and F-actin depolymerization, then inducing growth cone retraction [53]. Nogo-A-D20 interacts with S1PR2 and maybe some other unidentified receptors and inactivates CREB that regulates the transcription of target genes as well as dephosphorylates F-actin and activates ROCK [18,83,115]. Other proteins such as FGF-2 also interact with NgR1, resulting in the inhibition of FGF-2's binding to its receptor [99,100].…”

“…In addition,in the sensory DRG neurons, the Nogo-66 receptor homolog NgR2, a member of the Nogo-66 receptor NgR family which consists of three structurally related proteins called NgR1-3, also shows its potent effect on the epidermal innervation by interacting with versican which may synergize with Nogo-A as a repellent factor to sensory axons [56,81,82]. Additionally, a recent on-line published work reveals that neuronal Nogo-A in retinal ganglion cells could participate in enhancing axonal sprouting, possibly by cis-interaction with Nogo receptors at the cell membrane that may counteract trans-Nogo-A signaling [83]. This study suggests that inactivating Nogo-A in glia while preserving neuronal Nogo-A expression may be a successful strategy to promote axonal regeneration in the CNS.…”