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  • Review Article
  • Published:

Adhesion G protein-coupled receptors in nervous system development and disease

Key Points

  • The family of adhesion G protein-coupled receptors (aGPCRs) represents the second largest class of GPCRs, and aGPCRs have a functional 'division of labour' in the nervous system in that the amino terminus mediates adhesion while the carboxyl terminus transduces downstream GPCR signalling.

  • aGPCRs are required for a variety of developmental events in the nervous system from neural tube closure and synaptogenesis to myelination and beyond. Mutations in various aGPCRs are implicated in brain malformations and neural developmental disorders.

  • aGPCRs control cell–cell and cell–matrix interactions in addition to signalling events during neural development.

  • aGPCRs signal via a tethered agonist mechanism.

  • aGPCRs in the nervous system are likely to be mechanically sensitive.

Abstract

Members of the adhesion G protein-coupled receptor (aGPCR) class have emerged as crucial regulators of nervous system development, with important implications for human health and disease. In this Review, we discuss the current understanding of aGPCR functions during key steps in neural development, including cortical patterning, dendrite and synapse formation, and myelination. We focus on aGPCR modulation of cell–cell and cell–matrix interactions and signalling to control these varied aspects of neural development, and we discuss how impaired aGPCR function leads to neurological disease. We further highlight the emerging hypothesis that aGPCRs can be mechanically activated and the implications of this property in the nervous system.

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Figure 1: Molecular architecture of aGPCRs.
Figure 2: Organ-scale functions of aGPCRs.
Figure 3: Cellular-scale functions of aGPCRs.
Figure 4: Laminin 211 may facilitate mechanical activation of GPR126 in Schwann cell development.
Figure 5: The aGPCR latrophilin sensitizes mechanosensory neurons in Drosophila melanogaster.

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Acknowledgements

The authors thank their colleagues in the Adhesion GPCR Consortium (www.adhesiongpcr.org) for their continuous feedback on results and scientific concepts that are discussed in this Review. The authors apologize to all colleagues whose work could not be covered owing to scope and space restrictions. This work was supported by grants of the Deutsche Forschungsgemeinschaft (FOR 2149/P1+P3, SFB 1047/A5, SFB-TR 166/C3 and LA2861/7-1 to T.L.), the US National Institutes of Health (NS085201 and NS094164 to X.P. and NS079445 and HD080601 to K.R.M.), and the National Multiple Sclerosis Society (RG-1501-02577 to X.P. and Harry Weaver Neuroscience Fellowship to K.R.M.).

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Correspondence to Tobias Langenhan, Xianhua Piao or Kelly R. Monk.

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Glossary

Extracellular matrix

(ECM). A network of secreted molecules, including glycoproteins and polysaccharides. ECM molecules secreted by a cell remain closely associated to provide adhesive, signalling and structural functions.

Adhesion G protein-coupled receptors

(aGPCRs). A family of receptors within the GPCR superfamily structurally characterized by a large extracellular domain (ECD), a seven-transmembrane domain (7TM) and an intracellular domain (ICD). aGPCR ECDs often contain motifs that are involved in cell–cell and cell–matrix interactions.

GPCR autoproteolysis-inducing (GAIN) domain

An evolutionarily conserved domain (320 amino acids) shared by adhesion G protein-coupled receptors and polycystic kidney disease proteins. The GAIN domain is both necessary and sufficient for receptor autocleavage.

Stachel sequence

(Stalk). From the German word for 'stinger', the Stachel sequence is generated by adhesion G protein-coupled receptor (aGPCR) cleavage, is connected to the seven-transmembrane domain and functions as an intramolecular tethered agonist for aGPCRs.

Planar cell polarity

(PCP). The global polarized organization of cells within the plane of a tissue.

Polymicrogyria

A developmental brain malformation characterized by many small folds (gyri) in the cortex. Bilateral frontoparietal polymicrogyria (BFPP) and bilateral perisylvian polymicrogyria (BPPR) are subtypes of polymicrogyria caused by mutations in the adhesion G protein-coupled receptor gene GPR56.

Arthrogryposis multiplex congenita

A congenital disorder defined by the presence of at least two major joint contractures caused by reduced or absent fetal movement.

Basal lamina

A component of basement membranes that is linked to the basal side of cell membranes and comprises organized extracellular matrix molecules.

Metabotropic receptor

A membrane receptor that acts through second messengers.

Chordotonal organs

Peripheral compound mechanosensory organs in insects and other arthropods that perceive mechanical signals such as sound, touch and muscle stretch.

GPS motif

(GPCR proteolysis site motif). A small motif (50 amino acids) contained within the larger G protein-coupled receptor (GPCR) autoproteolysis-inducing (GAIN) domain of adhesion GPCRs and polycystic kidney disease proteins where receptor autocleavage occurs. Many adhesion GPCRs are autocleaved at the GPCR proteolysis site inside the motif. The GPS motif alone is necessary, but not sufficient, for receptor autocleavage.

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Langenhan, T., Piao, X. & Monk, K. Adhesion G protein-coupled receptors in nervous system development and disease. Nat Rev Neurosci 17, 550–561 (2016). https://doi.org/10.1038/nrn.2016.86

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