title: Hbp1 regulates the timing of neuronal differentiation during cortical development by controlling cell cycle progression.
abstract: In the developing mammalian brain, neural stem cells (NSCs) initially expand the progenitor pool by symmetric divisions. NSCs then shift from symmetric to asymmetric division and commence neurogenesis. Although the precise mechanisms regulating the developmental timing of this transition have not been fully elucidated, gradual elongation in the length of the cell cycle and coinciding accumulation of determinants that promote neuronal differentiation might function as a biological clock that regulates the onset of asymmetric division and neurogenesis. We conducted gene expression profiling of embryonic NSCs in the cortical regions and found that expression of high mobility group box transcription factor 1 (Hbp1) was upregulated during neurogenic stages. Induced conditional knockout mice of Hbp1, generated by crossing with Nestin-CreER(T2) mice, exhibited a remarkable dilatation of the telencephalic vesicles with a tangentially expanded ventricular zone and a thinner cortical plate containing reduced numbers of neurons. In these Hbp1-deficient mouse embryos, neural stem/progenitor cells continued to divide with a shorter cell cycle length. Moreover, downstream target genes of the Wnt signaling, such as cyclin D1 (Ccnd1) and c-jun (Jun), were upregulated in the germinal zone of the cortical regions. These results indicate that Hbp1 plays a crucial role in regulating the timing of cortical neurogenesis by elongating the cell cycle and that it is essential for normal cortical development.
authors.affiliation: Institute for Virus Research, Kyoto University, Shogoin-Kawahara, Sakyo-ku, Kyoto 606-8507, Japan Japan Science and Technology Agency, Core Research for Evolutional Science and Technology (CREST), 4-1-8 Honcho, Kawaguchi, Saitama 332-0012, Japan Graduate School of Medicine, Kyoto University, Kyoto 606-8501, Japan.
authors.forename: Naoki
authors.initials: N
authors.lastname: Watanabe
authors.affiliation: Institute for Virus Research, Kyoto University, Shogoin-Kawahara, Sakyo-ku, Kyoto 606-8507, Japan Japan Science and Technology Agency, Core Research for Evolutional Science and Technology (CREST), 4-1-8 Honcho, Kawaguchi, Saitama 332-0012, Japan Graduate School of Medicine, Kyoto University, Kyoto 606-8501, Japan Graduate School of Biostudies, Kyoto University, Kyoto 606-8501, Japan World Premier International Research Initiative-Institute for Integrated Cell-Material Sciences (WPI-iCeMS), Kyoto University, Kyoto 606-8501, Japan.
authors.forename: Ryoichiro
authors.initials: R
authors.lastname: Kageyama
authors.affiliation: Institute for Virus Research, Kyoto University, Shogoin-Kawahara, Sakyo-ku, Kyoto 606-8507, Japan Japan Science and Technology Agency, Core Research for Evolutional Science and Technology (CREST), 4-1-8 Honcho, Kawaguchi, Saitama 332-0012, Japan Graduate School of Medicine, Kyoto University, Kyoto 606-8501, Japan Graduate School of Biostudies, Kyoto University, Kyoto 606-8501, Japan tohtsuka@virus.kyoto-u.ac.jp.
authors.forename: Toshiyuki
authors.initials: T
authors.lastname: Ohtsuka
mesh_terms: D000818:Animals; D051778:Basic Helix-Loop-Helix Leucine Zipper Transcription Factors / Q000235:genetics / Q000378:metabolism; D002453:Cell Cycle / Q000235:genetics; D002454:Cell Differentiation / Q000235:genetics; D002465:Cell Movement / Q000235:genetics; D049109:Cell Proliferation; D002540:Cerebral Cortex / Q000166:cytology / Q000254:growth & development; D019938:Cyclin D1 / Q000378:metabolism; D005260:Female; D018507:Gene Expression Regulation, Developmental; D055785:Gene Knockdown Techniques; D006609:High Mobility Group Proteins / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*; D008813:Mice, Inbred ICR; D018345:Mice, Knockout; D009024:Morphogenesis; D058953:Neural Stem Cells / Q000166:cytology / Q000378:metabolism; D055495:Neurogenesis / Q000235:genetics; D009474:Neurons / Q000166:cytology* / Q000378:metabolism*; D012097:Repressor Proteins / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*; D016160:Retinoblastoma Protein / Q000378:metabolism; D013997:Time Factors; D015854:Up-Regulation / Q000235:genetics
chemical_list: D051778:Basic Helix-Loop-Helix Leucine Zipper Transcription Factors; C486329:Hbp1 protein, mouse; D006609:High Mobility Group Proteins; D012097:Repressor Proteins; D016160:Retinoblastoma Protein; D019938:Cyclin D1
keywords: Brain morphology; Cell cycle; Cortical development; Hbp1; Mouse; Neural stem cells; Neuronal differentiation