p600 regulates spindle orientation in apical neural progenitors and contributes to neurogenesis in the developing neocortex
Camille Belzil,
Naoyuki Asada,
Kei-ichiro Ishiguro,
Takeo Nakaya,
Kari Parsons,
Valentina Pendolino,
Gernot Neumayer,
Marina Mapelli,
Yoshihiro Nakatani,
Kamon Sanada,
Minh Dang Nguyen
Affiliations
Camille Belzil
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
Naoyuki Asada
Molecular Genetics Research Laboratory, Graduate School of Science, The University of Tokyo, Hongo 7-3-1, Bunkyo-ku, Tokyo, 113-0033, Japan
Kei-ichiro Ishiguro
Dana Farber Cancer Institute, 44 Binney Street, Smith Building 836, Boston, MA 02115, USA
Takeo Nakaya
Dana Farber Cancer Institute, 44 Binney Street, Smith Building 836, Boston, MA 02115, USA
Kari Parsons
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
Valentina Pendolino
European Institute of Oncology, Department of Experimental Oncology, Via Adamello, 16-20139 Milan, Italy
Gernot Neumayer
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
Marina Mapelli
European Institute of Oncology, Department of Experimental Oncology, Via Adamello, 16-20139 Milan, Italy
Yoshihiro Nakatani
Dana Farber Cancer Institute, 44 Binney Street, Smith Building 836, Boston, MA 02115, USA
Kamon Sanada
Molecular Genetics Research Laboratory, Graduate School of Science, The University of Tokyo, Hongo 7-3-1, Bunkyo-ku, Tokyo, 113-0033, Japan
Minh Dang Nguyen
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
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.
