Mitotic WNT signalling orchestrates neurogenesis in the developing neocortex. (25th August 2021)

• Record Type: Journal Article
• Authors: Da Silva, Fabio; Zhang, Kaiqing; Pinson, Anneline; Fatti, Edoardo; Wilsch‐Bräuninger, Michaela; Herbst, Jessica; Vidal, Valerie; Schedl, Andreas; Huttner, Wieland B; Niehrs, Christof
• Is Part Of: EMBO journal. Volume 40:Number 19(2021)
• Page Start: n/a
• Page End: n/a
• Publication Date: 2021-08-25
• Subjects: WNT signalling -- mitosis -- neurogenesis -- LRP6 -- microcephaly; Molecular biology -- Periodicals; 572.805
• DOI: 10.15252/embj.2021108041
• Languages: English
• ISSNs: 0261-4189

Abstract

Abstract: 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. SYNOPSIS: WNT/STOP (STabilization Of Proteins) signalling promotes neurogenesis in the embryonic mouse neocortex by regulating asymmetric cell division and Sox4/11 protein stabilization. These findings reveal that WNT/STOP, and not WNT/β‐catenin, is the major driver of cortical neurogenesis. WNT/STOP signalling regulates cell cycle progression and asymmetric cell division in neural progenitors. The neuronal differentiation factors Sox4 and Sox11 are direct GSK3 targets. Mitosis is essential for dictating neural progenitor cell fate in the embryonic mouse neocortex. WNT/STOP is the major WNT pathway driving neuronal differentiation of basal progenitors. Abstract : WNT/STOP (STabilization Of Proteins) signalling is the primary driver of neuronal differentiation of progenitor cells, while WNT/β‐catenin signalling predominantly regulates progenitor cell self‐renewal.