Importin Alpha Subtypes Determine Differential Transcription Factor Localization in Embryonic Stem Cells Maintenance

• Published in: Developmental cell Vol. 26; no. 2; pp. 123 - 135
• Main Authors: Yasuhara, Noriko, Yamagishi, Ryosuke, Arai, Yoshiyuki, Mehmood, Rashid, Kimoto, Chihiro, Fujita, Toshiharu, Touma, Kenichi, Kaneko, Azumi, Kamikawa, Yasunao, Moriyama, Tetsuji, Yanagida, Toshio, Kaneko, Hiroki, Yoneda, Yoshihiro
• Format: Journal Article
• Language: English
• Published: United States Elsevier Inc 29.07.2013
• Subjects: Active Transport, Cell Nucleus; Animals; beta Karyopherins - metabolism; Cell Differentiation; Cell Line; Cell Nucleus - metabolism; Embryonic Stem Cells - metabolism; Mice; Nerve Tissue Proteins - metabolism; Nuclear Localization Signals - metabolism; Nuclear Proteins - metabolism; Octamer Transcription Factor-3 - metabolism; Octamer Transcription Factor-6 - metabolism; POU Domain Factors - metabolism; Protein Binding; Signal Transduction
• ISSN: 1534-5807; 1878-1551
• DOI: 10.1016/j.devcel.2013.06.022

We recently demonstrated that the expression of the importin α subtype is switched from α2 to α1 during neural differentiation in mouse embryonic stem cells (ESCs) and that this switching has a major impact on cell differentiation. In this study, we report a cell-fate determination mechanism in which importin α2 negatively regulates the nuclear import of certain transcription factors to maintain ESC properties. The nuclear import of Oct6 and Brn2 was inhibited via the formation of a transport-incompetent complex of the cargo bound to a nuclear localization signal binding site in importin α2. Unless this dominant-negative effect was downregulated upon ESC differentiation, inappropriate cell death was induced. We propose that although certain transcription factors are necessary for differentiation in ESCs, these factors are retained in the cytoplasm by importin α2, thereby preventing transcription factor activity in the nucleus until the cells undergo differentiation. [Display omitted] •POU proteins bind different sites on importin α subtypes•An NLS binding site in importin α2 inhibits the nuclear import of Oct6•Importin α2 retains Oct6 in the cytoplasm of undifferentiated ESCs•Import inhibition by importin α is involved in maintenance of ESC properties Yasuhara et al. show that in ESCs, nuclear import of Oct6 and Brn2 is inhibited via formation of a transport-incompetent complex consisting of cargo bound to the importin α2 NLS. This inhibition of transport helps maintain ESC properties, preventing nuclear activity of these factors until cells undergo differentiation.