( b) The Wnt-PCP pathway based on findings from the Drosophila epithelia. β-catenin is then translocated into the nucleus, displacing the transcriptional repressor Groucho to regulate gene transcription together with the TCF (T cell factor) transcription factor. (ii) Activation of the Frizzled receptors by Wnts, in some cases with the help of the LRP5/6 co-receptor, relieves β-catenin from degradation. (i) In the absence of Wnts, the Axin-APC (Adenomatous polyposis coli)-GSK3β (glycogen synthase kinase 3β) complex promotes the proteasomal degradation of β-catenin. ( a) The β-catenin-dependent Wnt signalling. These Wnt signalling cascades will be examined in more detail in later sections that discuss individual aspects of axon or dendrite development. Numerous studies suggest that β-catenin-independent cascades play crucial roles in controlling axon and dendrite development. As a classical morphogen, Wnts regulate cell fate largely through the β-catenin-dependent transcriptional pathway. Adding to the complexity of Wnt signalling is its dependence on cellular and developmental contexts. Major pathways downstream of Wnt-Frizzled signalling include one that regulates gene transcription through β-catenin (so-called canonical Wnt or Wnt-β-catenin pathway) and those that require polarity molecules, cytoskeletal elements or calcium signalling but are otherwise independent of β-catenin ( figure 1 b,c). Second, highly branched pathways relay signals downstream of Dishevelleds, cytoplasmic scaffolds that Frizzled receptors engage after Wnt binding ( figure 1 b,c). First, the multiple homologues of Wnt ligands display relative, rather than absolute, binding specificity for the various Frizzled receptors, generating substantial promiscuity in ligand–receptor pairing. The complexity of Wnt signalling comes in two flavours. Palmitoylated Wnts bind Frizzleds, which are seven transmembrane proteins that serve as cognate Wnt receptors, with the help of the LRP5/6 co-receptor in certain cases ( figure 1 a). Present in metazoan species from cnidarians to primates, the Wnt family of secreted glycoproteins are well known for their diverse signalling functions. In this review, we focus on Wnts, an evolutionarily conserved family of morphogens that emerge as critical players in axon and dendrite development. Classical morphogens, such as Hedgehog (Hh), transforming growth factor β (TGF-β) and fibroblast growth factors (FGFs), also play important roles in guiding migrating neurons or axon growth cones that are distinct from their canonical functions in controlling cell fate. Morphogens are secreted proteins that specify cell fate depending on their concentration gradients. Representative examples include neurotrophic factors, axon guidance cues and cell adhesion molecules. Moreover, some molecules directly instruct the trajectory of axon and dendrites. These secreted or membrane-tethered molecules provide a permissive environment that allows neurites to develop and extend. In addition to genetic programmes governed by transcription factors that specify neuronal types and their wiring properties, extracellular signals are also instrumental in the construction of neural pathways. Proper functioning of the nervous system depends on highly accurate and specific connectivity of neuronal circuits.
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