[en] The role of WNT/β-catenin signalling in mouse neocortex development remains ambiguous. Most studies demonstrate that WNT/β-catenin regulates progenitor self-renewal but others suggest it can also promote differentiation. Here we explore the role of WNT/STOP signalling, which stabilizes proteins during G2/M by inhibiting glycogen synthase kinase (GSK3)-mediated protein degradation. We show that mice mutant for cyclin Y and cyclin Y-like 1 (Ccny/l1), key regulators of WNT/STOP signalling, display reduced neurogenesis in the developing neocortex. Specifically, basal progenitors, which exhibit delayed cell cycle progression, were drastically decreased. Ccny/l1-deficient apical progenitors show reduced asymmetric division due to an increase in apical-basal astral microtubules. We identify the neurogenic transcription factors Sox4 and Sox11 as direct GSK3 targets that are stabilized by WNT/STOP signalling in basal progenitors during mitosis and that promote neuron generation. Our work reveals that WNT/STOP signalling drives cortical neurogenesis and identifies mitosis as a critical phase for neural progenitor fate.
Disciplines :
Neurology
Author, co-author :
Da Silva, Fabio ; Division of Molecular Embryology, DKFZ, Heidelberg, Germany
Zhang, Kaiqing ; Division of Molecular Embryology, DKFZ, Heidelberg, Germany
Pinson, Anneline ; Max Planck Institute of Molecular Cell Biology and Genetics, Dresden, Germany
Fatti, Edoardo ; Division of Molecular Embryology, DKFZ, Heidelberg, Germany
Wilsch-Bräuninger, Michaela; Max Planck Institute of Molecular Cell Biology and Genetics, Dresden, Germany
Herbst, Jessica; Division of Molecular Embryology, DKFZ, Heidelberg, Germany
Vidal, Valerie; INSERM, CNRS, iBV, Université Côte d'Azur, Nice, France
Schedl, Andreas; INSERM, CNRS, iBV, Université Côte d'Azur, Nice, France
Huttner, Wieland B ; Max Planck Institute of Molecular Cell Biology and Genetics, Dresden, Germany
Niehrs, Christof ; Division of Molecular Embryology, DKFZ, Heidelberg, Germany ; Institute of Molecular Biology (IMB), Mainz, Germany
Language :
English
Title :
Mitotic WNT signalling orchestrates neurogenesis in the developing neocortex.
Expert technical help from the DKFZ core facilities for light microscopy, transgenics and the Central Animal Laboratory, and from the Biomedical Services Facility of the MPI‐CBG, is gratefully acknowledged. We thank Elizabeth Sock for providing the Sox4 and Sox11 antibodies and Andrei Glinka for help with antibody purification. We also thank Hyeyoon Lee for designing the graphical abstract. This work was supported by the Deutsche Forschungsgemeinschaft (DFG), SFB 873. FDS was supported by the EMBO long‐term fellowship ALTF 982‐2018.Expert technical help from the DKFZ core facilities for light microscopy, transgenics and the Central Animal Laboratory, and from the Biomedical Services Facility of the MPI-CBG, is gratefully acknowledged. We thank Elizabeth Sock for providing the Sox4 and Sox11 antibodies and Andrei Glinka for help with antibody purification. We also thank Hyeyoon Lee for designing the graphical abstract. This work was supported by the Deutsche Forschungsgemeinschaft (DFG), SFB 873. FDS was supported by the EMBO long-term fellowship ALTF 982-2018.
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