Semaphorin3A Regulates Neuronal Polarization by Suppressing Axon Formation and Promoting Dendrite Growth

SummarySemaphorin 3A (Sema3A) is a secreted factor known to guide axon/dendrite growth and neuronal migration. We found that it also acts as a polarizing factor for axon/dendrite development in cultured hippocampal neurons. Exposure of the undifferentiated neurite to localized Sema3A suppressed its differentiation into axon and promoted dendrite formation, resulting in axon formation away from the Sema3A source, and bath application of Sema3A to polarized neurons promoted dendrite growth but suppressed axon growth. Fluorescence resonance energy transfer (FRET) imaging showed that Sema3A elevated the cGMP but reduced cAMP and protein kinase A (PKA) activity, and its axon suppression is attributed to the downregulation of PKA-dependent phosphorylation of axon determinants LKB1 and GSK-3β. Downregulating Sema3A signaling in rat embryonic cortical progenitors via in utero electroporation of siRNAs against the Sema3A receptor neuropilin-1 also resulted in polarization defects in vivo. Thus, Sema3A regulates the earliest step of neuronal morphogenesis by polarizing axon/dendrite formation.

► Localized Sema3A suppressed axon differentiation and promoted dendrite development
► Sema3A elevated cytoplasmic cGMP and reduced cAMP/PKA activities via PDE4 activation
► Sema3A-induced cGMP inhibited PKA-dependent phosphorylation of LKB1 and GSK-3beta
► Downregulating Sema3A disrupted polarization of developing cortical neurons in vivo