Polarity Acquisition in Cortical Neurons Is Driven by Synergistic Action of Sox9-Regulated Wwp1 and Wwp2 E3 Ubiquitin Ligases and Intronic miR-140

The establishment of axon-dendrite polarity is fundamental for radial migration of neurons during cortex development of mammals. We demonstrate that the E3 ubiquitin ligases WW-Containing Proteins 1 and 2 (Wwp1 and Wwp2) are indispensable for proper polarization of developing neurons. We show that knockout of Wwp1 and Wwp2 results in defects in axon-dendrite polarity in pyramidal neurons, and their aberrant laminar cortical distribution. Knockout of miR-140, encoded in Wwp2 intron, engenders phenotypic changes analogous to those upon Wwp1 and Wwp2 deletion. Intriguingly, transcription of the Wwp1 and Wwp2/miR-140 loci in neurons is induced by the transcription factor Sox9. Finally, we provide evidence that miR-140 supervises the establishment of axon-dendrite polarity through repression of Fyn kinase mRNA. Our data delineate a novel regulatory pathway that involves Sox9–[Wwp1/Wwp2/miR-140]-Fyn required for axon specification, acquisition of pyramidal morphology, and proper laminar distribution of cortical neurons. [Display omitted] •The ubiquitin ligases Wwp1 and Wwp2 are essential for neuronal polarity acquisition•Wwp2 and Wwp2-intron-encoded miR-140 synergistically regulate neuronal development•miR-140 represses Fyn expression during neuronal development•Sox9 drives expression of Wwp1, Wwp2, and miR-140 in neurons Ambrozkiewicz et al. describe a synergistic signaling pathway that involves Sox9-driven expression of the E3 ubiquitin ligases Wwp1 and Wwp2 and of Wwp2-intron-encoded miR-140, and miR-140-dependent control of Fyn expression to regulate axon-dendrite polarity in developing neurons.