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

•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.