Nogo limits neural plasticity and recovery from injury
Introduction
The longitudinal growth of nerve fibers, the regeneration of injured axons and the structural plasticity of axons and dendrites are confined to very short distances and limited spatial dimensions in the adult mammalian central system (CNS). The successful regeneration of adult CNS axons of multiple origins into peripheral nerve grafts placed into spinal cord, brain or optic nerve over centimeter distances emphasized the key role of factors from the local tissue microenvironment in determining the extent of growth [1]. Twenty years ago, specific neurite growth inhibitory factors, many of which were enriched in myelin, were discovered. Nogo-A, the myelin proteins, MAG and OMgp, several semaphorins and ephrins as well as chondroitin sulphate proteoglycans have been identified [2]. For many of these molecules the detailed expression pattern in the adult CNS, the possible interplay between single factors, as well as their in vivo roles in the intact or injured adult CNS are not well characterized yet. More information is available for the membrane protein Nogo-A; some key concepts and the most recent literature on Nogo-A will be summarized in this short review.
Section snippets
Nogo-A interacts with a multisubunit receptor complex
Fragment analyses and binding studies showed that the 1200 aa protein Nogo-A contains more than one growth inhibiting domain (Figure 1). The 66 aa extracellular loop between the two C-terminal intramembrane segments binds to a GPI-linked, LRR-containing membrane protein called NgR1. Signaling is induced by a receptor complex containing the membrane proteins p75 and/or Troy and the LRR-protein Lingo1 [3, 4, 5]. An alternative Nogo-66 receptor is PirB. PirB is expressed at low or undetectable
Nogo-A destabilizes the cytoskeleton and suppresses the cellular growth program
Growth cones collapse and neurite elongation stops upon contact with Nogo-A in a rho/ROCK dependent way. Interestingly, internalization of Nogo-A was shown to be required for these effects in growth cones of hippocampal neurons [16]. Integrin function is also affected by Nogo-A [11], and activation of integrins can overcome the Nogo-A mediated growth inhibition [17•]. The actin cytoskeleton-based lamellipodia and filopodia of growth cones are affected at an early stage of the collapse.
Suppression of Nogo-A/Nogo receptor signaling enhances repair after CNS injury
Spinal cord injuries affecting up to half of the spinal cord diameter or strokes destroying only part of the motor cortex often have a good prognosis with substantial spontaneous functional recovery in animals and humans. Compensatory sprouting of intact fiber systems and formation of new circuits including indirect ‘detour’ pathways are currently emerging as important mechanisms underlying these functional recovery processes [22, 23, 24]. The factors which trigger and guide growing fibers,
Nogo-A and NgR1 signaling titrates experience-dependent plasticity
It is abundantly clear that interruption of the Nogo-A to Nogo-66 receptor pathway increases functional recovery after injury by a combination of neuronal plasticity, short range sprouting and axonal regeneration. The observation of anatomical rearrangements far from the injury site and by uninjured pathways raises the question of the natural role of this Nogo pathway for anatomical stability in the adult nervous system (Figure 2).
It is well appreciated that experience-dependent neural
Stability of adult synaptic anatomy is dependent on Nogo-A and NgR1 signaling
A broad range of studies have implicated Nogo-A and NgR1 in determining the formation and stability of synaptic morphology over longer time scales. In hippocampal slices, post-synaptic dendritic spine architecture, as well as axonal length, was found to depend on Nogo-A and NgR1 signaling [20•]. Interruption of Nogo-A or NgR1 expression produced more immature appearing dendritic spines. Genetic deletion of NgR1, 2 and 3 demonstrated a key role for these proteins as a brake on synaptogenesis
Behavioral consequences of Nogo-A and NgR1 signaling
Without Nogo-A or NgR1 signaling, adolescent critical periods for experience dependent plasticity remain open and the recovery from CNS injury is enhanced. Are these data associated with altered behavior? One clue may come from the ability of high levels of neuronal excitation to suppress NgR1 levels [62•, 65], perhaps allowing anatomical plasticity to follow periods of hyperexcitation. In a study of mice expressing elevated levels of NgR1 [65], learning was intact but lasting memory formation
Conclusions
The Nogo-A and NgR1 signaling cascade have been studied extensively with regard to neurological trauma. Blockade of these pathways leads to greater functional recovery through a combination of neural plasticity, sprouting and axonal regeneration. The benefits of interrupting Nogo-A or NgR1 are observed in a broad spectrum of preclinical models and are beginning clinical evaluation. Recent molecular studies have demonstrated a signaling pathway for a second domain of Nogo-A that involves the
Conflict of interest
SMS is a co-founder of Axerion Therapeutics, seeking to develop NgR-based and PrP-based therapeutics.
References and recommended reading
Papers of particular interest, published within the period of review, have been highlighted as:
• of special interest
•• of outstanding interest
Acknowledgements
We acknowledge support from the National Institutes of Health and the Falk Medical Research Trust to SMS, and from the Swiss National Science Foundation and the Christopher and Dana Reeve Foundation to MES.
References (69)
Nogo and axon regeneration
Curr Opin Neurobiol
(2004)- et al.
Myelin associated inhibitors: a link between injury-induced and experience-dependent plasticity
Exp Neurol
(2012) - et al.
A multi-domain fragment of nogo-a protein is a potent inhibitor of cortical axon regeneration via nogo receptor 1
J Biol Chem
(2011) - et al.
Pincher-generated nogo-a endosomes mediate growth cone collapse and retrograde signaling
J Cell Biol
(2010) - et al.
Integrin activation promotes axon growth on inhibitory chondroitin sulfate proteoglycans by enhancing integrin signaling
J Neurosci
(2011) - et al.
Plasticity of motor systems after incomplete spinal cord injury
Nat Rev Neurosci
(2001) - et al.
Anti-nogo-a antibody treatment promotes recovery of manual dexterity after unilateral cervical lesion in adult primates — re-examination and extension of behavioral data
Eur J Neurosci
(2009) - et al.
Lingo-1 antagonists as therapy for multiple sclerosis: In vitro and in vivo evidence
Expert Opin Biol Ther
(2008) - et al.
The neurite outgrowth inhibitor nogo a is involved in autoimmune-mediated demyelination
Nat Neurosci
(2004) - et al.
Degenerative and regenerative responses of injured neurons in the central nervous system of adult mammals
Phil Trans R Soc B
(1991)
Central nervous system regeneration inhibitors and their intracellular substrates
Mol Neurobiol
Functions of nogo proteins and their receptors in the nervous system
Nat Rev Neurosci
Spatio-temporal expression of paired immunoglobulin-like receptor-b in the adult mouse brain after focal cerebral ischaemia
Brain Injury
The nogo-66 receptor ngr1 is required only for the acute growth cone-collapsing but not the chronic growth-inhibitory actions of myelin inhibitors
J Neurosci
Cartilage acidic protein-1b (lotus), an endogenous nogo receptor antagonist for axon tract formation
Science
Ngr1 and ngr3 are receptors for chondroitin sulfate proteoglycans
Nat Neurosci
The n-terminal domain of nogo-a inhibits cell adhesion and axonal outgrowth by an integrin-specific mechanism
J Neurosci
The sphingolipid receptor s1pr2 is a receptor for nogo-a repressing synaptic plasticity
PLoS Biol
Gpr50 interacts with neuronal nogo-a and affects neurite outgrowth
Mol Cell Neurosci
Olfactomedin 1 interacts with the nogo a receptor complex to regulate axon growth
J Biol Chem
Ldl receptor-related protein-1 is a sialic-acid-independent receptor for myelin-associated glycoprotein that functions in neurite outgrowth inhibition by mag and cns myelin
J Cell Sci
Neuronal nogo-a regulates glutamate receptor subunit expression in hippocampal neurons
J Neurochem
Neuronal nogo-a modulates growth cone motility via rho-gtp/limk1/cofilin in the unlesioned adult nervous system
J Biol Chem
Nogo-a stabilizes the architecture of hippocampal neurons
J Neurosci
Neutralization of the membrane protein nogo-a enhances growth and reactive sprouting in established organotypic hippocampal slice cultures
Eur J Neurosci
The injured spinal cord spontaneously forms a new intraspinal circuit in adult rats
Nat Neurosci
Restoring voluntary control of locomotion after paralyzing spinal cord injury
Science
Neuronal intrinsic mechanisms of axon regeneration
Annu Rev Neurosci
Excessive activation of mtor in postnatally generated granule cells is sufficient to cause epilepsy
Neuron
Mtor signaling in glioblastoma: lessons learned from bench to bedside
Neuro-Oncology
Anti-nogo on the go: from animal models to a clinical trial
Ann N Y Acad Sci
Axonal growth therapeutics: regeneration or sprouting or plasticity?
Trends Neurosci
Mag and omgp synergize with nogo-a to restrict axonal growth and neurological recovery after spinal cord trauma
J Neurosci
Combined genetic attenuation of myelin and semaphorin-mediated growth inhibition is insufficient to promote serotonergic axon regeneration
J Neurosci
Cited by (286)
Amino-terminal proteolytic fragment of the axon growth inhibitor Nogo-A (Rtn4A) is upregulated by injury and promotes axon regeneration
2023, Journal of Biological ChemistryModels and approaches to comprehend and address glial inflammation following spinal cord injury
2023, Drug Discovery TodayGrowth factors and molecular-driven plasticity in neurological systems
2023, Handbook of Clinical Neurology