title: p600 regulates spindle orientation in apical neural progenitors and contributes to neurogenesis in the developing neocortex.
abstract: Apical neural progenitors (aNPs) drive neurogenesis by means of a program consisting of self-proliferative and neurogenic divisions. The balance between these two manners of division sustains the pool of apical progenitors into late neurogenesis, thereby ensuring their availability to populate the brain with terminal cell types. Using knockout and in utero electroporation mouse models, we report a key role for the microtubule-associated protein 600 (p600) in the regulation of spindle orientation in aNPs, a cellular event that has been associated with cell fate and neurogenesis. We find that p600 interacts directly with the neurogenic protein Ndel1 and that aNPs knockout for p600, depleted of p600 by shRNA or expressing a Ndel1-binding p600 fragment all display randomized spindle orientation. Depletion of p600 by shRNA or expression of the Ndel1-binding p600 fragment also results in a decreased number of Pax6-positive aNPs and an increased number of Tbr2-positive basal progenitors destined to become neurons. These Pax6-positive aNPs display a tilted mitotic spindle. In mice wherein p600 is ablated in progenitors, the production of neurons is significantly impaired and this defect is associated with microcephaly. We propose a working model in which p600 controls spindle orientation in aNPs and discuss its implication for neurogenesis.
authors.affiliation: Hotchkiss Brain Institute, University of Calgary, Departments of Clinical Neurosciences, Cell Biology and Anatomy, and Biochemistry and Molecular Biology, 3330 Hospital Drive NW, Heritage Medical Research Building, Calgary, AB T2N 4N1, Canada.
authors.forename: Camille
authors.initials: C
authors.lastname: Belzil
authors.affiliation: Molecular Genetics Research Laboratory, Graduate School of Science, The University of Tokyo, Hongo 7-3-1, Bunkyo-ku, Tokyo, 113-0033, Japan.
authors.forename: Naoyuki
authors.initials: N
authors.lastname: Asada
authors.affiliation: Dana Farber Cancer Institute, 44 Binney Street, Smith Building 836, Boston, MA 02115, USA Institute of Molecular and Cellular Biosciences, University of Tokyo, 1-1-1 Yayoi, Tokyo 113-0032, Japan.
authors.forename: Kei-Ichiro
authors.initials: K
authors.lastname: Ishiguro
authors.affiliation: Dana Farber Cancer Institute, 44 Binney Street, Smith Building 836, Boston, MA 02115, USA.
authors.forename: Takeo
authors.initials: T
authors.lastname: Nakaya
authors.affiliation: Hotchkiss Brain Institute, University of Calgary, Departments of Clinical Neurosciences, Cell Biology and Anatomy, and Biochemistry and Molecular Biology, 3330 Hospital Drive NW, Heritage Medical Research Building, Calgary, AB T2N 4N1, Canada.
authors.forename: Kari
authors.initials: K
authors.lastname: Parsons
authors.affiliation: European Institute of Oncology, Department of Experimental Oncology, Via Adamello, 16-20139 Milan, Italy.
authors.forename: Valentina
authors.initials: V
authors.lastname: Pendolino
authors.affiliation: Hotchkiss Brain Institute, University of Calgary, Departments of Clinical Neurosciences, Cell Biology and Anatomy, and Biochemistry and Molecular Biology, 3330 Hospital Drive NW, Heritage Medical Research Building, Calgary, AB T2N 4N1, Canada.
authors.forename: Gernot
authors.initials: G
authors.lastname: Neumayer
authors.affiliation: European Institute of Oncology, Department of Experimental Oncology, Via Adamello, 16-20139 Milan, Italy.
authors.forename: Marina
authors.initials: M
authors.lastname: Mapelli
authors.affiliation: Dana Farber Cancer Institute, 44 Binney Street, Smith Building 836, Boston, MA 02115, USA.
authors.forename: Yoshihiro
authors.initials: Y
authors.lastname: Nakatani
authors.affiliation: Molecular Genetics Research Laboratory, Graduate School of Science, The University of Tokyo, Hongo 7-3-1, Bunkyo-ku, Tokyo, 113-0033, Japan mdnguyen@ucalgary.ca kamon_sanada@gen.s.u-tokyo.ac.jp.
authors.forename: Kamon
authors.initials: K
authors.lastname: Sanada
authors.affiliation: Hotchkiss Brain Institute, University of Calgary, Departments of Clinical Neurosciences, Cell Biology and Anatomy, and Biochemistry and Molecular Biology, 3330 Hospital Drive NW, Heritage Medical Research Building, Calgary, AB T2N 4N1, Canada mdnguyen@ucalgary.ca kamon_sanada@gen.s.u-tokyo.ac.jp.
authors.forename: Minh Dang
authors.initials: MD
authors.lastname: Nguyen
keywords: Apical neural progenitors; Ndel1; Neurogenesis; Spindle orientation; UBR4; p600