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The cadherin superfamily in neuronal connections and interactions

Key Points

  • The organization of neuronal circuits involves a number of processes that require cell–cell recognition and contacts. Cadherins are a family of cell–cell adhesion molecules comprising more than 100 members in vertebrates, which are grouped into subfamilies including classic cadherins, Flamingo/CELSRs and protocadherins, and are thought to have roles in various steps of neuronal cell interactions.

  • N-cadherin and other vertebrate classic cadherins are essential not only for early morphogenesis of neural tissues but also for correct axon migration towards target areas, and for the extension of neuronal dendrites.

  • Drosophila melanogaster N-cadherin (DN-cadherin) has been shown to be crucial for the formation of axonal connections with target neurons in both the visual and olfactory systems, and also for confining dendritic arborizations to specific glomeruli in these systems. The activity of DN-cadherin during the axon targeting seems to be controlled by cytoplasmic proteins including leukocyte antigen-related-receptor protein tyrosine phosphatase (LAR).

  • Flamingo, a seven-pass transmembrane cadherin, is required for the correct targeting of retinal axons in visual circuits in D. melanogaster. A vertebrate homologue of Flamingo, CELSR2, regulates dendritic arbor patterning in the cerebellum, and another homologue, CELSR3, is important for axon tract formation.

  • Some protocadherins, which show a large diversification due to a unique gene organization, seem to be involved in synapse formation and neuronal survival. However, the biological roles of this subfamily remain largely unknown.

  • In conclusion, members of the cadherin superfamily control axon–target recognition and connections, as well as other types of neuronal interactions in a subfamily-specific manner.

Abstract

Neural development and the organization of complex neuronal circuits involve a number of processes that require cell–cell interaction. During these processes, axons choose specific partners for synapse formation and dendrites elaborate arborizations by interacting with other dendrites. The cadherin superfamily is a group of cell surface receptors that is comprised of more than 100 members. The molecular structures and diversity within this family suggest that these molecules regulate the contacts or signalling between neurons in a variety of ways. In this review I discuss the roles of three subfamilies — classic cadherins, Flamingo/CELSRs and protocadherins — in the regulation of neuronal recognition and connectivity.

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Figure 1: Schematic drawings of cadherin superfamily members.
Figure 2: Effects of classic cadherin dysfunction on retinal morphogenesis and neurite extension.
Figure 3: Effects of DN-cadherin or Flamingo mutation on axon projections in the lamina of the optic lobe.
Figure 4: Effects of DN-cadherin or Flamingo mutation on retinal axon targeting in the medulla.
Figure 5: Cooperation between the nectin and cadherin adhesion systems for establishing synaptic contacts.
Figure 6: Effects of CELSR deficiencies.

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Acknowledgements

I thank T. R. Clandinin, C. Desplan, H. Togashi and T. Usui for providing the original drawings for schematic illustrations; A. Goffinet, Y. Iwai, I. Masai, K. Tanabe and T. Uemura for providing photographs; S. Hirano for data analysis; and S. Ito for her help in preparing figures. Work in the laboratory was supported by the program Grants-in-Aid for Specially Promoted Research of the Ministry of Education, Science, Sports, and Culture of Japan.

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Glossary

Dendritic field

The area covered by dendritic arborizations of a neuron.

Adherens junction

Protein complexes that occur at cell–cell junctions. They are composed of the cadherin–catenin complexes, and characterized by accumulation of actin filaments at their cytoplasmic side.

Neuroepithelial stage

The earliest stage in the developing CNS. The neuroepithelium is a layer of cells with epithelium-like morphologies, which give rise to a diverse array of neural cells during development.

Ommatidium

A unit of the compound eye of insects. Each ommatidium contains a cluster of photoreceptor cells and functionally provides the brain with one picture element.

Lamina

Neuropil structure that makes up part of the optic lobe of insects. Out of eight retinal axons, the R1–R6 axons innervate L1–L5 neurons in the lamina. The lamina L1–L5 neurons relay R1–R6 input to the medulla.

Medulla

Neuropil structure that makes up part of the optic lobe of insects. Out of eight retinal axons the R7 and R8 axons innervate the medulla, which also receives input from the lamina L1–L5 neurons.

Fascicle

A slender bundle of nerve fibres.

Defasciculation

The disentanglement of individual axon fibres from a bundle of fibres, called a fascicle or tract, which allows them to migrate in separate directions.

Glomerulus

In the nervous system, an anatomically discrete module that receives input from other neurons.

Planar cell polarity

(PCP). The property of epithelial cells polarizing along the plane of the epithelium.

Hemisegment

The animal body is segmented along the rostrocaudal axis, as seen in the insects. A hemisegment represents half of a symmetrical segment from either side of the body.

Stereocilia

Mechanosensing organelles of hair cells. As hearing sensors, stereocilia are lined up in the Organ of Corti within the cochlea of the inner ear.

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Takeichi, M. The cadherin superfamily in neuronal connections and interactions. Nat Rev Neurosci 8, 11–20 (2007). https://doi.org/10.1038/nrn2043

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