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Functions of Nogo proteins and their receptors in the nervous system

Key Points

  • The membrane protein Nogo-A is a major player in the neurite growth-inhibitory and regeneration-inhibitory effects exerted by myelin in the mammalian brain and spinal cord. In the injured CNS, neutralization or blockade of Nogo-A enhances regeneration, compensatory fibre sprouting and functional recovery. In the intact nervous system, a number of physiological functions of Nogo proteins have been recently discovered, as discussed in this Review.

  • Nogo proteins and the related reticulon (RTN)1-3 proteins consist of a highly conserved, 200-amino acid carboxy-terminal RTN domain and non-homologous amino-terminal extensions of various lengths. The neurite growth-inhibitory protein Nogo-A appeared in evolution for the first time in frogs and is present in all higher vertebrates. Two active sites are present; a Nogo-A-specific domain and a 66-amino acid domain that lies between the transmembrane and intramembrane parts of the RTN domain. Nogo-A is highly enriched in the nervous system, in oligodendrocytes and myelin at adult stages, and in neurons and precursor cells during development. The short proteins Nogo-B and Nogo-C are not inhibitory and occur in various tissues, including the nervous system.

  • Two binding sites are currently known for the Nogo-66 sequence, the Nogo receptor 1 (NgR1) and the membrane protein paired immunoglobulin-like receptor B (PIRB). Both receptors also interact with other ligands, however. The receptor for the Nogo-A specific active site remains to be characterized. Rho activation followed by destabilizing effects on the cytoskeleton are obligatory steps in the postreceptor signalling and effector pathway that leads to the collapse of neurite growth cones. Several additional proteins are associated with what is probably a multisubunit receptor complex for Nogo-A.

  • Nogo-B, by interaction with a Nogo-B receptor (NGBR), influences vascular endothelial cells and smooth muscle cells, which hyperproliferate after vascular lesions in Nogo-A and Nogo-B double knockout mice. The function of Nogo-C is currently still unknown.

  • During CNS development, Nogo-A and its receptors are expressed in cortical precursors and affect their migration. Many projection neurons in the central and peripheral nervous systems express Nogo-A during axonal outgrowth; its neutralization or knockout enhances axonal fasciculation and influences branching. NgR1 and the shorter Nogo forms also have guidance and fasciculation functions in zebrafish, a lower vertebrate.

  • In the adult CNS, oligodendrocyte and myelin Nogo-A suppresses the growth programme of adult neurons, probably by a retrograde action on the cell bodies. Locally, neurite growth is dampened by the growth cone collapsing actions of Nogo-A. Nogo-A thus acts as a stabilizer of the adult CNS neuronal network and wiring. Ablation of Nogo-A or NgR1 accordingly enhances plastic rearrangements of CNS connections, extending the so-called 'critical period' far into adult ages, for example, for visual cortex plasticity. The schizophrenia-like behaviour of Nogo-A knockout mice and the associations found between psychiatric disorders and mutations in the genes encoding Nogo or NgR1 may be based on similar functions.

  • In addition to its cell surface expression, high amounts of Nogo are also present intracellularly. In neurons, its interaction with β-secretase points to a role in the regulation of amyloid precursor protein (APP) processing. Manipulations of Nogo have indicated a structural role for Nogo in the endoplasmic reticulum (ER) and the nuclear membrane. Interactions with proteins involved in cell survival and apoptosis have also been observed.

  • Various approaches aimed at suppressing Nogo-A or NgR1 actions have been used following injury of the adult spinal cord or brain. Acute functional suppression and, with more variable effects, chronic genetic deletion enhance regenerative sprouting and growth of various CNS tract systems. In addition, spared fibre systems have shown enhanced compensatory sprouting; both these processes were associated with substantial improvements of the behavioural recovery of lost functions in rodents and monkeys. These results illustrate the important growth-suppressive role of Nogo-A in the adult mammalian CNS.

Abstract

The membrane protein Nogo-A was initially characterized as a CNS-specific inhibitor of axonal regeneration. Recent studies have uncovered regulatory roles of Nogo proteins and their receptors — in precursor migration, neurite growth and branching in the developing nervous system — as well as a growth-restricting function during CNS maturation. The function of Nogo in the adult CNS is now understood to be that of a negative regulator of neuronal growth, leading to stabilization of the CNS wiring at the expense of extensive plastic rearrangements and regeneration after injury. In addition, Nogo proteins interact with various intracellular components and may have roles in the regulation of endoplasmic reticulum (ER) structure, processing of amyloid precursor protein and cell survival.

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Figure 1: Domains, localization, binding partners and signalling of Nogo proteins.
Figure 2: Common intracellular pathways but opposite effects of Nogo-A and neurotrophins.
Figure 3: Functions of Nogo-A in the developing and adult CNS.
Figure 4: Role of NgR or Nogo-A/Nogo-B in restricting the developmental plasticity in the visual cortex.

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Acknowledgements

The author thanks his laboratory colleagues; in particular A. Buchli, A. Joset, V. Pernet, B. Tews and R. Willi for critically reading the manuscripts. The author's work is supported by grants from the Swiss National Science Foundation (3100AO-122,527/1), the National Center for Competence in Research 'Neural Plasticity & Repair' of the Swiss National Science Foundation, the Spinal Cord Consortium of the Christopher and Dana Reeve Foundation, several EU Framework 7 projects, and the International Foundation of Research in Paraplegia.

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Glossary

Compartmentalized cultures

Neurons are grown in the middle chamber of a three-chamber culture system. Their neurites are guided into the side chambers under a Teflon ring divider or through microfluidic channels. Neurites can be treated with substances and subsequently analysed separately from the cell bodies.

Tangential migration

A mode of neuron migration that is non-radial. Most interneurons immigrate tangentially into the forebrain cortex from a proliferation zone in the basal ganglia region.

Cortical plate

The upper part of the developing cerebral cortex, where neurons end their migration and start to assemble into the distinct neuronal layers that will form the future adult cortex.

Subplate

A transient layer of cells in the fetal brain that lies beneath the cortical plate.

Intermediate zone

A transient layer in the developing cortex through which neurons migrate on their way from the proliferative zone to the cortical plate. With maturation, this zone is replaced by the subcortical white matter.

Morpholinos

Antisense oligonucleotides that block gene expression.

Tubular ER

A major part of the endoplasmic reticulum (ER) of cells that is characterized by a tubular shape, as opposed to the flat ER cisterns that compose the nuclear membrane, or the Nissl bodies in synthetically highly active neurons.

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Schwab, M. Functions of Nogo proteins and their receptors in the nervous system. Nat Rev Neurosci 11, 799–811 (2010). https://doi.org/10.1038/nrn2936

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