Signaling mechanisms of non-conventional axon guidance cues: the Shh, BMP and Wnt morphogens

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Highlights

  • The morphogens Shh, BMPs and Wnts are also axon guidance molecules.

  • Shh, BMPs and Wnts do not guide axons via their canonical signaling pathways.

  • Instead, morphogens act via non-canonical signaling pathways to guide axons.

  • These non-canonical pathways involve SFKs, PI3K, Ca2+, PKCs and PCP proteins.

During nervous system development, axons, led by the growth cone, must navigate to their destinations. Axon guidance cues are molecules in the extracellular environment that attract or repel axons to guide them along their correct trajectory. The non-conventional axon guidance cues include morphogens of the Hedgehog, TGF-β/BMP, and Wnt/Wgl families. Canonical signaling by morphogens regulates transcription in the nucleus to specify cell fate. Recent studies have begun to elucidate how these morphogens can also direct growth cone turning, using signaling mechanisms that diverge from their canonical signaling pathways. Furthermore, in addition to directly guiding axons, some non-conventional guidance cues such as Sonic hedgehog also modulate the response of axons to other guidance cues, adding another level of regulation to axon guidance.

Introduction

During nervous system development, neurons project axons over long distances to reach their appropriate targets for correct neural circuit formation. They are guided by axon guidance cues present in the extracellular environment which can attract or repel axons. The classical axon guidance cues include the netrins, semaphorins, Slits, and ephrins [1]. About ten years ago, it was discovered that the morphogens Sonic hedgehog (Shh), bone morphogenetic proteins (BMPs), and Wnts can also guide axons. Now we are beginning to uncover the diversity of receptors (Table 1) and signaling pathways involved in morphogen-mediated axon guidance. The canonical Shh, BMP, and Wnt signaling pathways employed in cell fate specification signal to the nucleus, yet axon guidance by morphogens involves local changes at the growth cone. We will discuss how the signaling pathways used by morphogens to guide axons diverge from the canonical signaling pathways used by morphogens to specify cell fate, focusing on the action of Shh, BMPs, and Wnts in vertebrates. Some morphogens, such as BMPs and Wnts regulate axon growth as well as guidance [2, 3], but due to length constraints this review will focus primarily on the guidance mechanisms of these molecules. We will also discuss the crosstalk between axon guidance cues.

Section snippets

Sonic hedgehog

In canonical Shh signaling, binding of Shh to its receptors Ptch1, together with either Boc, Cdon, or Gas1, relieves inhibition of the transmembrane protein Smoothened (Smo), an activator of the pathway [4, 5, 6] (Figure 1a). Smo activation leads to Gli2 activation, its translocation to the nucleus and transcription of target genes involved in cell fate specification. Shh is also an important axon guidance cue for commissural neurons [7, 8, 9••], retinal ganglion cells (RGCs) [10, 11, 12, 13]

BMPs

BMPs are members of the TGF-β superfamily. Canonical BMP signaling typically involves ligand-induced recruitment and activation of a BMP receptor complex consisting of type I and type II receptor subunits. BMP binding leads to the phosphorylation and nuclear translocation of Smad proteins that then regulate the transcription of target genes that control cell fate specification [24] (Figure 3a). BMPs also guide commissural axons through type I and type II BMP receptors. However, there are

Wnts

Wnts are a large family of ligands that can activate at least three different signal transduction pathways [29, 30]. The canonical β-catenin-dependent pathway is triggered by the interaction of Wnt with Frizzled (Fz) and LRP5 or LRP6 (Figure 4a). This stabilizes cytoplasmic β-catenin which then enters the nucleus to associate with the transcription factors TCF (T cell factor) and LEF (lymphoid enhancer-binding factor) to regulate the transcription of target genes. This pathway is primarily

Crosstalk between axon guidance cues

Shh not only directly guides axons but can also modulate the response of axons to other guidance cues. For example, Shh at the floorplate, together with NrCAM and gdnf, activates the repulsive response of commissural axons to semaphorins, which allows for the correct exit of commissural axons from the floorplate [22, 40, 41].

In the chick, Wnts are also axon guidance cues for post-crossing commissural axons. However, in contrast to rodents, the expression of Wnt does not vary along the A-P axis [

Conclusions and Perspectives

Research on non-conventional axon guidance cues has thus far highlighted the many instances where Shh, BMPs and Wnts guide axons (Table 1), underscoring their fundamental role in axon guidance and nervous system development. Recently, a new non-conventional axon guidance cue was discovered. The angiogenic factor VEGF-A, best known for its ability to stimulate endothelial cell proliferation and migration during blood vessel growth, is also an attractive guidance cue for spinal cord commissural

References and recommended reading

Papers of particular interest, published within the period of review, have been highlighted as:

  • • of special interest

  • •• of outstanding interest

Acknowledgements

Work performed in the Charron lab is supported by grants from the Canadian Institutes of Health Research (CIHR), the Fonds de Recherche en Santé du Québec (FRSQ), and the Canada Foundation for Innovation (CFI). FC is a FRSQ Chercheur-Boursier. We thank L. Izzi for assistance with the figures.

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