p75 Neurotrophin receptor signaling regulates growth cone filopodial dynamics through modulating RhoA activity

The mechanisms by which neurotrophins regulate growth cone motility are unclear. We investigated the role of the p75 neurotrophin receptor (p75(NTR)) in mediating neurotrophin-induced increases in filopodial length. Our data demonstrate that neurotrophin binding to p75(NTR) is necessary and sufficient to regulate filopodial dynamics. Furthermore, retinal and dorsal root ganglion growth cones from p75 mutant mice are insensitive to neurotrophins but display enhanced filopodial lengths comparable with neurotrophin-treated wild-type growth cones. This suggests unoccupied p75(NTR) negatively regulates filopodia length. Furthermore, p75(NTR) regulates RhoA activity to mediate filopodial dynamics. Constitutively active RhoA blocks neurotrophin-induced increases in filopodial length, whereas inhibition of RhoA enhances filopodial lengths, similar to neurotrophin treatment. BDNF treatment of retinal neurons results in reduced RhoA activity. Furthermore, p75 mutant neurons display reduced levels of activated RhoA compared with wild-type counterparts, consistent with the enhanced filopodial lengths observed on mutant growth cones. These observations suggest that neurotrophins regulate filopodial dynamics by depressing the activation of RhoA that occurs through p75(NTR) signaling.