A FOXO–Pak1 transcriptional pathway controls neuronal polarity (original) (raw)

1. Brice Gaudillière1,
2. Yue Yang1,2,5,
3. Yoshiho Ikeuchi1,5,
4. Tomoko Yamada1,5,
5. Sara DiBacco1,
6. Judith Stegmüller1,6,
7. Ulrich Schüller3,7,
8. Dervis A. Salih4,
9. David Rowitch3,8,
10. Anne Brunet4 and
11. Azad Bonni1,2,9
12. 1Department of Pathology, Harvard Medical School, Boston, Massachusetts 02115, USA;
13. 2Program in Neuroscience, Harvard Medical School, Boston, Massachusetts 02115, USA;
14. 3Department of Pediatric Oncology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, Massachusetts 02115, USA;
15. 4Department of Genetics, Stanford University, Stanford, California 94305, USA

• ↵6 Present addresses: Max-Planck-Institute of Experimental Medicine, Hermann-Rein-Str. 3, 37075 Göttingen, Germany;
• ↵7 Center for Neuropathology and Prion Research, Ludwig-Maximilians-Universität, Feodor-Lynen-St 23, 81377 Munich, Germany;
• ↵8 Department of Pediatrics, Department of Neurological Surgery, and Howard Hughes Medical Institute, University of California at San Francisco, San Francisco, CA 94143, USA.

1. ↵5 These authors contributed equally to this work.

Abstract

Neuronal polarity is essential for normal brain development and function. However, cell-intrinsic mechanisms that govern the establishment of neuronal polarity remain to be identified. Here, we report that knockdown of endogenous FOXO proteins in hippocampal and cerebellar granule neurons, including in the rat cerebellar cortex in vivo, reveals a requirement for the FOXO transcription factors in the establishment of neuronal polarity. The FOXO transcription factors, including the brain-enriched protein FOXO6, play a critical role in axo–dendritic polarization of undifferentiated neurites, and hence in a switch from unpolarized to polarized neuronal morphology. We also identify the gene encoding the protein kinase Pak1, which acts locally in neuronal processes to induce polarity, as a critical direct target gene of the FOXO transcription factors. Knockdown of endogenous Pak1 phenocopies the effect of FOXO knockdown on neuronal polarity. Importantly, exogenous expression of Pak1 in the background of FOXO knockdown in both primary neurons and postnatal rat pups in vivo restores the polarized morphology of neurons. These findings define the FOXO proteins and Pak1 as components of a cell-intrinsic transcriptional pathway that orchestrates neuronal polarity, thus identifying a novel function for the FOXO transcription factors in a unique aspect of neural development.

Keywords:

• FOXO
• neuronal polarity
• Pak1
• transcription
• axons
• dendrites

Footnotes

• ↵9 Corresponding author.
  E-MAIL azad_bonni{at}hms.harvard.edu; FAX (617) 432-4101.

• Article is online at http://www.genesdev.org/cgi/doi/10.1101/gad.1880510.

• Supplemental material is available at http://www.genesdev.org.

• • Received October 30, 2009.
  • Accepted February 26, 2010.

• Copyright © 2010 by Cold Spring Harbor Laboratory Press

•