The role of WWP-family E3 ubiquitin ligases in neuronal development and function
Final Report Abstract
In mammalian brains, neurons develop in five steps, 1) neurogenesis, 2) multipolar-bipolar transition (i.e. polarity formation), 3) migration, 4) neurite extension and branching, and 5) synapse formation. Disruptions of these processes could result in severe human disorders. Especially, genes involved in steps 2) and 3) are causative of heterotopia, microcephaly, and lissencephaly (e.g. DCX, RELN, Lis1). Proper coordination of rearrangement of cytoskeleton and membrane traffic by numbers of signaling pathways is essential for these steps. Recent emergent evidence suggests protein ubiquitination plays substantial roles in neuronal development. Ubiquitination is mediated buy three classes of enzymes, E1 ubiquitin activating enzyme, E2 ubiquitin conjugating enzyme, and E3 ubiquitin ligases, Among them, E3 ubiquitin ligases play critical roles in determining substrate specificity of ubiquitination. In the project supported by DFG, we demonstrate that two E3 ubiquitin ligase genes, Wwp1 and Wwp2 are key players for the polarity formation and migration of neurons. Unexpectedly, knockout or knockdown of miR-140 gene encoded in an intron of Wwp2 resulted in phenotypic changes analogous to those of Wwp1 and Wwp2 double knockout neurons. We identified and characterized Sox9 as a transcription factor responsible for RNA synthesis for the expression of Wwp1, Wwp2, and miR-140. Functionally, Sox9 also plays an important role in polarity formation and neuronal migration as a coordinator of Wwp1, Wwp2, and miR-140. This result is reported in Research News of Max Planck Society: https://www.mpg.de/12453737/neuronal-migration-polarization
Publications
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(2017) ELKS1 localizes the synaptic vesicle priming protein bMunc13-2 to a specific subset of active zones. JCB 216, 1143-1161
Kawabe, H., Mitkovski, M., Kaeser, P.S., Hirrlinger, J., Opazo, F., Nestvogel, D., Kalla, S., Fejtova, A., Verrier, S.E., Bungers, S.R., Cooper, B.H., Varoqueaux, F., Wang, Y., Nehring, R.B., Gundelfinger, E.D., Rosenmund, C., Rizzoli, S.O., Südhof, T.C., Rhee, J.S., and Brose, N.
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(2017) Formation and Maintenance of Functional Spines in the Absence of Presynaptic Glutamate Release. Neuron 94, 304-311
Sigler, A., Oh, W.C., Imig, C., Altas, B., Kawabe, H., Cooper, B.H., Kwon, H.B., Rhee, J.S., and Brose, N.
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(2018) Deletion of LRRTM1 and LRRTM2 in adult mice impairs basal AMPA receptor transmission and LTP in hippocampal CA1 pyramidal neurons. Proc. Natl. Acad. Sci. U.S.A. 115, E5382-E5389
Bhouri, M., Morishita, W., Temkin, P., Goswami, D., Kawabe, H., Brose, N., Südhof, T.C., Craig, A.M., Siddiqui, T.J., and Malenka, R.
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(2018) Polarity Acquisition in Cortical Neurons Is Driven by Synergistic Action of Sox9-Regulated Wwp1 and Wwp2 E3 Ubiquitin Ligases and Intronic miR-140. Neuron 100, 1097-1115
Ambrozkiewicz, M.C., Schwark, M., Kishimoto-Suga, M., Borisova, E., Hori, K., Salazar-Lázaro, A., Rusanova, A., Altas, B., Piepkorn, L., Bessa, P., Schaub, T., Zhang, X., Rabe, T., Ripamonti, S., Rosário, M., Akiyama, H., Jahn, O., Kobayashi, T., Hoshino, M., Tarabykin, V., and Kawabe, H.
