A neuron is a polarized cell with a somatodendritic domain and an axon. Yi et al. (see also Dwyer and Winckler) investigated whether signaling through the transforming growth factor–β (TGF-β) pathway was involved in axon formation. Binding of TGF-β to the type II TGF-β receptor (TβR2) induces association of TβR2 with the type I TGF-β receptor (TβR1) and activation of the kinase domain of TβR1. The authors found that conditional ablation of Tgfbr2 in neuronal precursors in the ventricular zone in embryonic day 14.5 (E14.5) mouse embryos resulted in neurons that did not form axons and that did not migrate through the intermediate zone. Conditional ablation of Tgfbr2 of neurons in organotypic slice culture also prevented axon formation and migration to the cortical plate. Dissociated hippocampal neurons that were grown in vitro in the presence of the TβR1 inhibitor SB-43154 lacked an axon that was positive for the axonal marker tau-1, whereas those overexpressing a constitutively active form of TβR2 had multiple tau-1–positive axons. Addition of exogenous TGF-β through conjugated beads or TGF-β substrate induced neurite extension or formation of multiple axons, respectively. The polarity protein Par6 colocalized with TβR1 in brain slices and hippocampal neurons and coimmunoprecipitated with TβR1 from rat forebrain. TβR2 phosphorylates Ser345 of Par6, and overexpression of a Par6 form that cannot be phosphorylated (Ser345→Ala; S345A) prevented axon formation, whereas overexpression of a Par6 form that mimicked phosphorylation (Ser345→Glu; S345E) resulted in axon formation. TβR2-deficient neurons formed axons when overexpressing Par6-S345E, but not Par6-S345A, although overexpression of Par6-S345E did not rescue migration defects. Thus, TGF-β signaling triggers phosphorylation of Par6 and induces neurites to elongate and develop into axons.
J. J. Yi, A. P. Barnes, R. Hand, F. Polleux, M. D. Ehlers, TGF-β signaling specifies axons during brain development. Cell 142, 144–157 (2010). [PubMed]
N. D. Dwyer, B. Winckler, TGF-β receptors PAR-ticipate in axon formation. Cell 142, 21–23 (2010). [PubMed]