title: Radmis, a novel mitotic spindle protein that functions in cell division of neural progenitors.
abstract: Developmental dynamics of neural stem/progenitor cells (NSPCs) are crucial for embryonic and adult neurogenesis, but its regulatory factors are not fully understood. By differential subtractive screening with NSPCs versus their differentiated progenies, we identified the radmis (radial fiber and mitotic spindle)/ckap2l gene, a novel microtubule-associated protein (MAP) enriched in NSPCs. Radmis is a putative substrate for the E3-ubiquitin ligase, anaphase promoting complex/cyclosome (APC/C), and is degraded via the KEN box. Radmis was highly expressed in regions of active neurogenesis throughout life, and its distribution was dynamically regulated during NSPC division. In embryonic and perinatal brains, radmis localized to bipolar mitotic spindles and radial fibers (basal processes) of dividing NSPCs. As central nervous system development proceeded, radmis expression was lost in most brain regions, except for several neurogenic regions. In adult brain, radmis expression persisted in the mitotic spindles of both slowly-dividing stem cells and rapid amplifying progenitors. Overexpression of radmis in vitro induced hyper-stabilization of microtubules, severe defects in mitotic spindle formation, and mitotic arrest. In vivo gain-of-function using in utero electroporation revealed that radmis directed a reduction in NSPC proliferation and a concomitant increase in cell cycle exit, causing a reduction in the Tbr2-positive basal progenitor population and shrinkage of the embryonic subventricular zone. Besides, radmis loss-of-function by shRNAs induced the multipolar mitotic spindle structure, accompanied with the catastrophe of chromosome segregation including the long chromosome bridge between two separating daughter nuclei. These findings uncover the indispensable role of radmis in mitotic spindle formation and cell-cycle progression of NSPCs.
authors.affiliation: Laboratory for Molecular Neurobiology, Graduate School of Human Sciences, Waseda University, Tokorozawa, Saitama, Japan.
authors.forename: Takahito
authors.initials: T
authors.lastname: Yumoto
authors.forename: Kazuhiko
authors.initials: K
authors.lastname: Nakadate
authors.forename: Yuki
authors.initials: Y
authors.lastname: Nakamura
authors.forename: Yoshinobu
authors.initials: Y
authors.lastname: Sugitani
authors.forename: Reiko
authors.initials: R
authors.lastname: Sugitani-Yoshida
authors.forename: Shuichi
authors.initials: S
authors.lastname: Ueda
authors.forename: Shin-ichi
authors.initials: S
authors.lastname: Sakakibara
mesh_terms: D000705:Anaphase / Q000502:physiology; D000818:Animals; D001483:Base Sequence; D001921:Brain / Q000378:metabolism* / Q000502:physiology; D018797:Cell Cycle Proteins / Q000378:metabolism; D049109:Cell Proliferation; D002478:Cells, Cultured; D020090:Chromosome Segregation / Q000502:physiology; D057809:HEK293 Cells; D006801:Humans; D008297:Male; D051379:Mice; D008813:Mice, Inbred ICR; D008869:Microtubule-Associated Proteins / Q000378:metabolism*; D008938:Mitosis / Q000502:physiology*; D008969:Molecular Sequence Data; D041681:NIH 3T3 Cells; D058953:Neural Stem Cells / Q000378:metabolism* / Q000502:physiology; D055495:Neurogenesis / Q000502:physiology; D008941:Spindle Apparatus / Q000378:metabolism* / Q000502:physiology; D013234:Stem Cells / Q000378:metabolism* / Q000502:physiology; D043743:Ubiquitin-Protein Ligase Complexes / Q000378:metabolism; D044767:Ubiquitin-Protein Ligases / Q000378:metabolism
chemical_list: D018797:Cell Cycle Proteins; D008869:Microtubule-Associated Proteins; D043743:Ubiquitin-Protein Ligase Complexes; D044767:Ubiquitin-Protein Ligases