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Signalling in neural development

WNTS in the vertebrate nervous system: from patterning to neuronal connectivity

Key Points

  • WNT proteins are important mediators of intercellular communication. WNTs signal through their Frizzled (FZ) receptors to activate the cytoplasmic scaffolding protein Dishevelled (DVL). WNTs can also signal through the tyrosine kinase-related receptor RYK, which interacts with FZ and DVL. Downstream of DVL, the WNT pathway diverges into at least three branches: the canonical or WNT/β-catenin pathway, the planar cell polarity (PCP) pathway and the WNT/calcium pathway. Several lines of evidence indicate that these pathways can also bifurcate, increasing the complexity for signalling.

  • In the embryonic nervous system, WNTs regulate diverse cellular processes, including cell proliferation and fate, cell polarity and movement, and programmed cell death. WNTs can influence tissue organization and growth by functioning locally, in an autocrine manner or on immediately adjacent cells, and can also act at a distance, by generating a gradient across a tissue. During early development, an anterior to posterior (A–P) WNT gradient regulates the formation of anterior brain structures. Regulation of WNT signalling is accomplished at two levels: through extracellular antagonists that bind to WNTs or to their receptors, and by intracellular factors that are expressed or activated in anterior regions of the neural tube. Later in development, a sharper WNT signalling gradient defines the final organization of the mature CNS. Concomitantly with the A–P specification of the neural tube, WNTs regulate dorsoventral (D–V) patterning from the forebrain to the spinal cord.

  • WNT signalling can also influence neuronal behaviour by controlling axon pathfinding and branching. It has been shown that WNTs can function as repulsive or attractive signals. WNT4 functions, through FZ3, as an attractive guidance cue to regulate spinal commissural axons. In the cerebellum, WNT7A regulates axonal remodelling and branching through activation of a divergent canonical pathway. WNT–DVL signalling regulates microtubule organization and stability in developing axons. By contrast, in dendrites the non-canonical pathway regulates dendritic length and branching through DVL, Rac and c-Jun amino (N)-terminal kinase (JNK). These findings indicate that different WNT pathways are activated in different neuronal compartments.

  • After axons make contact with their target, synapses are assembled — a process that requires crosstalk between the pre- and postsynaptic cells. In the cerebellum, WNT7A functions as a retrograde signal that modulates synapse formation and maturation. Recent studies have indicated that WNTs might regulate the formation of synapses in different brain areas. The expression of WNTs and their receptors in adult animals raises the interesting possibility that WNT signalling might modulate synaptic connectivity.

  • During embryonic patterning, progenitor cells can read and interpret a gradient of WNTs. Similarly, axons could use a WNT gradient as a positional value or coordinate to establish the distance to their targets. This read-out mechanism would allow axons to prepare themselves for changes in navigation or to accumulate synaptic proteins in preparation for synaptic assembly.

Abstract

WNT signalling has a key role in early embryonic patterning through the regulation of cell fate decisions, tissue polarity and cell movements. In the nervous system, WNT signalling also regulates neuronal connectivity by controlling axon pathfinding, axon remodelling, dendrite morphogenesis and synapse formation. Studies, from invertebrates to mammals, have led to a considerable understanding of WNT signal transduction pathways. This knowledge provides a framework for the study of the mechanisms by which WNTs regulate diverse neuronal functions. Manipulation of the WNT pathways could provide new strategies for nerve regeneration and neuronal circuit modulation.

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Figure 1: The three main branches of the WNT signalling pathway.
Figure 2: WNT signalling regulates patterning of the vertebrate neural tube.
Figure 3: WNTs regulate dorsal patterning of the spinal cord.
Figure 4: WNTs regulate the behaviour of axons.
Figure 5: WNT signalling stimulates dendrite morphogenesis.
Figure 6: WNTs regulate the formation of central synapses.

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Acknowledgements

We would like to thank D. Wilkinson and S. Wilson for helpful discussions and comments on the manuscript and members of our lab. We would also like to thank A. Brennan for discussions on spinal cord patterning. Our work is funded by The Wellcome Trust and the Biotechnology and Biological Sciences Research Council.

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Correspondence to Patricia C. Salinas.

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DATABASES

Entrez Gene

AXIN

BMP6

BMP7

Celsr1

DKK1

Dvl1

Dvl2

FZ3

Fz4

GBX2

GSK3β

KREMEN1

KREMEN2

Lef1

LRP5

LRP6

NT3

OTX2

PAK1

SHH

SIX3

Tcf3

Tcf3b

Tlc

Wnt1

WNT2B

Wnt3

WNT3A

WNT5A

WNT7A

WNT7B

Wnt8b

Wnt10b

FURTHER INFORMATION

Wnt Homepage

Salinas's Homepage

Glossary

NEURAL INDUCTION

A process by which the epithelium differentiates into the prospective neural plate by inductive signals from the dorsal mesoderm.

PLURIPOTENCY

The ability of cell to differentiate into a wide range of cell types depending on the environment. It must be distinguished from totipotency, which describes cells that can differentiate into any type of cell, including germ cells.

GSK3β

Glycogen synthase kinase 3 is a serine/threonine kinase. Two isoforms, α and β, which are encoded by different genes, have been described. The D. melanogaster homologue is Shaggy (SGG), a negative regulator of WG signalling.

LOSS-OF-FUNCTION

Mutations that lead to a decrease or total loss of the function of a gene.

NEURAL TUBE

Structure that forms by the upward movement and fusion of cells at the edge of the neural plate. The neural tube is divided into four main compartments in the A–P axis: the forebrain, midbrain, hindbrain and spinal cord.

BMPs

Bone morphogenetic proteins are members of the transforming growth factorβ family of secreted signalling molecules.

FGFs

Fibroblast growth factors are secreted signalling molecules.

A–P AND D–V AXES

The anterior to posterior axis runs from the head to the tail of a vertebrate embryo. The dorsoventral axis runs from the back to the stomach of an embryo.

FOREBRAIN

The most rostral structure of the neural tube. It is subdivided into the telencephalon, which gives rise to the cerebrum, hippocampus and olfactory lobes, and the diencephalon, which gives rise to the thalamic and hypothalamic regions.

MIDBRAIN

Also called mesencephalon, this is a region of the neural tube that gives rise to the anterior cerebellum, optic lobes and tectum.

HINDBRAIN

Also called the rhombencephalon, this is an area rostral to the spinal cord that gives rise to the posterior part of the cerebellum, pons and medulla.

MORPHOLINOS

Antisense oligos that block gene expression by interfering with the translation initiation complex or with RNA splicing.

NEURAL PLATE

Neural epithelial cells that form in the early embryo after neuronal induction and give rise to the nervous system.

SONIC HEDGEHOG

(SHH). Sonic hedgehog proteins are members of the hedgehog family of secreted proteins that are involved in early embryonic patterning.

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Ciani, L., Salinas, P. WNTS in the vertebrate nervous system: from patterning to neuronal connectivity. Nat Rev Neurosci 6, 351–362 (2005). https://doi.org/10.1038/nrn1665

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