RP58 Regulates the Multipolar-Bipolar Transition of Newborn Neurons in the Developing Cerebral Cortex
Chiaki Ohtaka-Maruyama,
Shinobu Hirai,
Akiko Miwa,
Julian Ik-Tsen Heng,
Hiroshi Shitara,
Rie Ishii,
Choji Taya,
Hitoshi Kawano,
Masataka Kasai,
Kazunori Nakajima,
Haruo Okado
Affiliations
Chiaki Ohtaka-Maruyama
Department of Brain Development and Neural Regeneration, Neural Development Project, Tokyo Metropolitan Institute of Medical Science, 2-1-6 Kamikitazawa, Setagaya-ku, Tokyo 156-8506, Japan
Shinobu Hirai
Department of Brain Development and Neural Regeneration, Neural Development Project, Tokyo Metropolitan Institute of Medical Science, 2-1-6 Kamikitazawa, Setagaya-ku, Tokyo 156-8506, Japan
Akiko Miwa
Department of Brain Development and Neural Regeneration, Neural Development Project, Tokyo Metropolitan Institute of Medical Science, 2-1-6 Kamikitazawa, Setagaya-ku, Tokyo 156-8506, Japan
Julian Ik-Tsen Heng
Australian Regenerative Medicine Institute, Monash University, Clayton, Victoria 3800, Australia
Hiroshi Shitara
The Basic Technology Research Center, Animal Research Division, Laboratory for Transgenic Technology, Tokyo Metropolitan Institute of Medical Science, 2-1-6 Kamikitazawa, Setagaya-ku, Tokyo 156-8506, Japan
Rie Ishii
The Basic Technology Research Center, Animal Research Division, Laboratory for Transgenic Technology, Tokyo Metropolitan Institute of Medical Science, 2-1-6 Kamikitazawa, Setagaya-ku, Tokyo 156-8506, Japan
Choji Taya
The Basic Technology Research Center, Animal Research Division, Laboratory for Transgenic Technology, Tokyo Metropolitan Institute of Medical Science, 2-1-6 Kamikitazawa, Setagaya-ku, Tokyo 156-8506, Japan
Hitoshi Kawano
Department of Brain Development and Neural Regeneration, Laboratory of Neural Regeneration, Tokyo Metropolitan Institute of Medical Science, 2-1-6 Kamikitazawa, Setagaya-ku, Tokyo 156-8506, Japan
Masataka Kasai
Center for Stem Cell and Regenerative Medicine, Institute of Medical Science, The University of Tokyo 4-6-1 Shirokanedai, Minato-ku, Tokyo108-8639, Japan
Kazunori Nakajima
Department of Anatomy, Keio University School of Medicine, 35 Shinanomachi, Shinjuku-ku, Tokyo 160-8582, Japan
Haruo Okado
Department of Brain Development and Neural Regeneration, Neural Development Project, Tokyo Metropolitan Institute of Medical Science, 2-1-6 Kamikitazawa, Setagaya-ku, Tokyo 156-8506, Japan
Accumulating evidence suggests that many brain diseases are associated with defects in neuronal migration, suggesting that this step of neurogenesis is critical for brain organization. However, the molecular mechanisms underlying neuronal migration remain largely unknown. Here, we identified the zinc-finger transcriptional repressor RP58 as a key regulator of neuronal migration via multipolar-to-bipolar transition. RP58−/− neurons exhibited severe defects in the formation of leading processes and never shifted to the locomotion mode. Cre-mediated deletion of RP58 using in utero electroporation in RP58flox/flox mice revealed that RP58 functions in cell-autonomous multipolar-to-bipolar transition, independent of cell-cycle exit. Finally, we found that RP58 represses Ngn2 transcription to regulate the Ngn2-Rnd2 pathway; Ngn2 knockdown rescued migration defects of the RP58−/− neurons. Our findings highlight the critical role of RP58 in multipolar-to-bipolar transition via suppression of the Ngn2-Rnd2 pathway in the developing cerebral cortex.
