FoxO6 affects Plxna4-mediated neuronal migration during mouse cortical development

  • Proc Natl Acad Sci U S A. 2016 Nov 8;113(45):E7087-E7096. doi: 10.1073/pnas.1609111113.
Ricardo H Paap  1 ,  Saskia Oosterbroek  1 ,  Cindy M R J Wagemans  1 ,  Lars von Oerthel  1 ,  Raymond D Schellevis  2 ,  Annemarie J A Vastenhouw-van der Linden  1 ,  Marian J A Groot Koerkamp  3 ,  Marco F M Hoekman  4 ,  Marten P Smidt  4
Affiliations
  • 1. Swammerdam Institute for Life Sciences, University of Amsterdam, 1098 XH Amsterdam, The Netherlands.
  • 2. Brain Center Rudolf Magnus, University Medical Center Utrecht, 3584 CX Utrecht, The Netherlands.
  • 3. Microarray Facility, Department of Molecular Cancer Research, University Medical Center Utrecht, 3584 CX Utrecht, The Netherlands.
  • 4. Swammerdam Institute for Life Sciences, University of Amsterdam, 1098 XH Amsterdam, The Netherlands; [email protected] [email protected].
PMID: 27791111 DOI: 10.1073/pnas.1609111113
Abstract

The forkhead transcription factor FoxO6 is prominently expressed during development of the murine neocortex. However, its function in cortical development is as yet unknown. We now demonstrate that cortical development is altered in FoxO6+/- and FoxO6-/- mice, showing migrating neurons halted in the intermediate zone. Using a FoxO6-directed siRNA approach, we substantiate the requirement of FoxO6 for a correct radial migration in the developing neocortex. Subsequent genome-wide transcriptome analysis reveals altered expression of genes involved in cell adhesion, axon guidance, and gliogenesis upon silencing of FoxO6 We then show that FoxO6 binds to DAF-16-binding elements in the Plexin A4 (Plxna4) promoter region and affects Plxna4 expression. Finally, ectopic Plxna4 expression restores radial migration in FoxO6+/- and siRNA-mediated knockdown models. In conclusion, the presented data provide insights into the molecular mechanisms whereby transcriptional programs drive cortical development.

Keywords
FoxO6; Plxna4; cortex; development; radial migration.