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

Neuron 2018 Dec 05

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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. Copyright © 2018 Elsevier Inc. All rights reserved.

Citation

Mateusz C Ambrozkiewicz, Manuela Schwark, Mika Kishimoto-Suga, Ekaterina Borisova, Kei Hori, Andrea Salazar-Lázaro, Alexandra Rusanova, Bekir Altas, Lars Piepkorn, Paraskevi Bessa, Theres Schaub, Xin Zhang, Tamara Rabe, Silvia Ripamonti, Marta Rosário, Haruhiko Akiyama, Olaf Jahn, Tatsuya Kobayashi, Mikio Hoshino, Victor Tarabykin, Hiroshi Kawabe. Polarity Acquisition in Cortical Neurons Is Driven by Synergistic Action of Sox9-Regulated Wwp1 and Wwp2 E3 Ubiquitin Ligases and Intronic miR-140. Neuron. 2018 Dec 05;100(5):1097-1115.e15