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Chemokine receptors: signposts to brain development and disease

Key Points

  • The 50 small proteins known as chemokines can be classified into four groups (α, β, γ and δ) according to the position of a pair of cysteines near their amino terminus.

  • Recent research indicates that chemokines and their receptors are important in the development of the nervous system. Their two principal functions are to direct the movement of progenitor cells to specific locations, and to ensure continued proliferation of progenitor cell populations.

  • In the embryonic cerebellum, the chemokine SDF-1 and its receptor, CXCR4, facilitate proliferation of granule cells and their migration to the internal granule layer, and are also involved in development of the dentate gyrus. MIP-1α/CCR1 chemokine signalling is probably important for the maturation of neurites and synapse formation.

  • Signalling through the chemokine Gro-α and its CXCR2 receptor directs the development of oligodendrocytes in the spinal cord. Chemokines also participate in the control of myelination in the peripheral nervous system.

  • Chemokines are widely expressed in the adult nervous system, and are up- or downregulated in response to stressful conditions and pathological stimuli. Their exact role in the adult nervous system is unknown, but data support their involvement in neuronal excitability, synaptic communication and cell survival.

  • Most chemokines are secreted from cells, and their effects are transduced through the activation of G-protein-coupled receptors. These effects can be mediated by interactions with other signalling systems, including the mitogen-activated protein kinase, Janus kinase (JAK) kinase, Sonic hedgehog, ephrin-B/Eph-B, pituitary adenylate cyclase activating protein and Slit/Robo pathways.

  • Chemokines are implicated in the manifestation of various brain disorders. They might, therefore, constitute novel therapeutic targets for the neuroinflammation associated with multiple sclerosis and Alzheimer's disease, human immunodeficiency virus 1 (HIV-1)-related cognitive, motor and sensory abnormalities, and brain neoplasias (for example, glial tumours and neuroblastomas).

Abstract

During the development of the nervous system, populations of progenitor cells that eventually become neurons and glia face the complex task of finding their way from their place of birth to their final destinations. What are the molecular processes that provide the information for guiding progenitor cells along their way? In this article, we discuss recent information indicating that chemokines and their receptors are of great importance in directing the proliferation and migration of immature neurons, glia and their precursors. Furthermore, chemokine receptor function in the nervous system continues to be important throughout adult life, and chemokines participate in various brain disorders, including AIDS dementia, neuroinflammatory disease and neuroplasia, making them important potential therapeutic targets in these cases.

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Figure 1: The different subfamilies of chemokine receptors and their chemokine ligands.
Figure 2: Individual neurons express several chemokine receptors.
Figure 3: Regulation of cerebellar granule cell progenitor development by SDF-1/CXCR4 signalling.
Figure 4: Expression of SDF-1 and CXCR4 in the developing mouse neocortex and hippocampus.
Figure 5: Regulation of oligodendrocyte precursor development by Gro-α/CXCR2 signalling in the developing spinal cord.
Figure 6: Diverse influences of SDF-1/CXCR4 signalling in the brain.
Figure 7: SDF-1/gp120 interactions and their possible role in human immunodeficiency virus 1 (HIV-1)-related neuropathology.

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DATABASES

LocusLink

CCR1

CXCR4

MIP-1α

SDF-1

Glossary

MUCIN

A highly glycosylated protein that is rich in serine or threonine for O-glycosylation.

TROPISM

The range of cells that can be productively infected by a virus.

MITOGEN

An agent that induces mitosis.

HILUS

A subdivision of the hippocampus that is rich in interneurons. It is located between the CA3 region and the dentate gyrus.

CAJAL–RETZIUS CELL

A transient pioneer neuron that is located in layer I of the developing neocortex and hippocampus.

LISSENCEPHALIC DISEASE

A congenital lack or underdevelopment of the convolutional pattern of the cerebral cortex, owing to a defect of development.

WALLERIAN DEGENERATION

A form of degeneration occurring in nerve fibres as a result of their division. Named after A. V. Waller, who published an account of it in 1850.

HELIX–LOOP–HELIX

A structural motif present in many transcription factors that is characterized by two α-helices separated by a loop.

PARACRINE

Signalling process that involves the secretion from a cell of molecules, which act on other cells in the immediate vicinity that express appropriate receptors, rather than acting on the same cell (autocrine signalling) or on remote cells (endocrine signalling).

SCAFFOLDING PROTEINS

Proteins that act as scaffolds for organizing different members of a signal transduction pathway.

NOCICEPTORS

Peripheral nerves, organs or mechanisms for the reception and transmission of painful or injurious stimuli.

PERTUSSIS TOXIN

The causative agent of whooping cough, pertussis toxin causes the persistent inhibition of Gi proteins by catalysing the ADP-ribosylation of the α-subunit.

PDZ DOMAIN

A peptide-binding domain that is important for the organization of membrane proteins, particularly at cell–cell junctions, including synapses. It can bind to the carboxyl termini of proteins or can form dimers with other PDZ domains. PDZ domains are named after the proteins in which these sequence motifs were originally identified (PSD95, Discs large, zona occludens 1).

MULTIPLE SCLEROSIS

A neurodegenerative disorder characterized by demyelination of central nervous system tracts. Symptoms depend on the site of demyelination and include sensory loss, weakness in leg muscles, speech difficulties, loss of coordination and dizziness.

MYELIN PALLOR

A manifestation of the destruction of myelinated axons.

ALLODYNIA

The perception of a stimulus as painful when previously the same stimulus was reported to be non-painful. As with hyperalgaesia, this term was derived from observations of humans in which verbal reporting was used to assess pain sensitivity, and so it is difficult to designate a change in pain sensitivity in animals as allodynic or hyperalgaesic.

GLIOMAS

Neuroectodermal tumours of neuroglial origin: include astrocytoma, oligodendroglioma and ependymoma derived from astrocytes, oligodendrocytes and ependymal cells, respectively. All infiltrate the adjacent brain tissue, but they do not metastasise.

AUTOCRINE

An agent that acts on the cell that produced it.

NEUROBLASTOMAS

Malignant tumours derived from primitive ganglion cells. Mainly a tumour of childhood. Most common sites are adrenal medulla and retroperitoneal tissue. The cells might partially differentiate into cells having the appearance of immature neurons.

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Tran, P., Miller, R. Chemokine receptors: signposts to brain development and disease. Nat Rev Neurosci 4, 444–455 (2003). https://doi.org/10.1038/nrn1116

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