title: Terminal differentiation of cortical neurons rapidly remodels RanGAP-mediated nuclear transport system.
abstract: Terminal differentiation of neurons is accompanied by irreversible exit from the cell cycle and expression of neuronal phenotypes. The molecular mechanism whereby committed neuronal progenitors lose their ability to reenter the cell cycle is largely unknown. Here, we report that the nuclear transport system is rapidly remodeled in primary cortical progenitor cells (CPCs) at the very beginning of neuronal terminal differentiation. High levels of Ran GTPase-activating protein 1 (RanGAP), a key regulator of the Ran GTP-GDP cycle, in primary CPCs are drastically reduced upon neuronal induction. Small ubiquitin-like modifier (SUMO)-2/3-conjugated RanGAP undergoes desumoylation and degradation in neuronally committed CPCs, where reduced RanGAP levels impede the nuclear import of nucleocytoplasmic shuttling proteins including the DNA replication initiation factor Cdc6. Furthermore, RNAi-mediated down-regulation of RanGAP expression in undifferentiated CPCs induces neuronal phenotypes including cell cycle exit. Our data suggest that remodeling of the RanGAP-mediated nuclear transport system plays a key role in cell cycle exit for terminal differentiation of cortical neurons.
authors.affiliation: Institute for Protein Research, Osaka University, Suita, Osaka, 565-0871, Japan.
authors.forename: Kazushiro
authors.initials: K
authors.lastname: Fujiwara
authors.affiliation: Institute for Protein Research, Osaka University, Suita, Osaka, 565-0871, Japan.
authors.forename: Koichi
authors.initials: K
authors.lastname: Hasegawa
authors.affiliation: National Institutes of Biomedical Innovation, Health and Nutrition, Ibaraki, Osaka, 567-0085, Japan.
authors.forename: Masahiro
authors.initials: M
authors.lastname: Oka
authors.affiliation: National Institutes of Biomedical Innovation, Health and Nutrition, Ibaraki, Osaka, 567-0085, Japan.
authors.forename: Yoshihiro
authors.initials: Y
authors.lastname: Yoneda
authors.affiliation: Institute for Protein Research, Osaka University, Suita, Osaka, 565-0871, Japan.
authors.forename: Kazuaki
authors.initials: K
authors.lastname: Yoshikawa
mesh_terms: D021581:Active Transport, Cell Nucleus; D000818:Animals; D001253:Astrocytes / Q000166:cytology; D002453:Cell Cycle; D002540:Cerebral Cortex / Q000166:cytology; D015536:Down-Regulation; D005260:Female; D020690:GTPase-Activating Proteins / Q000378:metabolism*; D051379:Mice; D008813:Mice, Inbred ICR; D055495:Neurogenesis
chemical_list: D020690:GTPase-Activating Proteins; C085844:Rangap1 protein, mouse