Wingless-type family member 3A triggers neuronal polarization via cross-activation of the insulin-like growth factor-1 receptor pathway.

BERNIS ME; OKSDATH M; DUPRAZ S; NIETO GUIL; FERNÁNDEZ MM; MALCHIODI EL; ROSSO SB; QUIROGA S

FRONTIERS IN HUMAN NEUROSCIENCE

FRONTIERS RES FOUND

Año: 2013 vol. 7 p. 1 - 12

1662-5161

Initial axonal elongation is one of the hallmarks of neuronal polarization. This phenomenon requires polarized activation of IGF-1 receptors (IGF-1r) and subsequent activation of the phosphatidylinositol 3 kinase (PI3k) pathway. Growth factors belonging to the wingeless-type family (Wnts) have been also implied in the regulation of axonal development. It is not known, however, if Wnts have any participation in the regulation of initial axonal outgrowth and the establishment of neuronal polarity. Here, we used cultured hippocampal pyramidal neurons and growth cone particles (GCPs) isolated from fetal rat brain to show that stimulation with the wingless family factor 3A (Wnt3a) is sufficient to promote neuronal polarization in the absence of IGF-1 or high levels of insulin. We also show that Wnt3a triggers the activation of IGF-1r and PI3k (polarized to one minor neurite) in neurons in stage 2 of development (i.e., not polarized). In addition, we show that the presence of activatable IGF-1 receptors and PI3k activation are necessary for Wnt3a polarizing effects. Surface plasmon resonance (SPR) experiments showed that Wnt3a does not bind specifically to the IGF-1r. Using crosslinking and immunoprecipitation experiments, we show that, in GCPs, stimulation with Wnt3a triggers the formation of a complex including IGF1r (active)-Wnt3a-Frizzled-7. We conclude that Wnt3a triggers polarization of hippocampal neurons via cross-activation of the IGF-1 receptor/PI3k pathway.