A FOXO-Pak1 transcriptional pathway controls neuronal polarity

TY - JOUR

T1 - A FOXO-Pak1 transcriptional pathway controls neuronal polarity

AU - de la Torre-Ubieta, Luis

AU - Gaudillière, Brice

AU - Yang, Yue

AU - Ikeuchi, Yoshiho

AU - Yamada, Tomoko

AU - DiBacco, Sara

AU - Stegmüller, Judith

AU - Schüller, Ulrich

AU - Salih, Dervis A

AU - Rowitch, David H

AU - Brunet, Anne

AU - Bonni, Azad

PY - 2010/4/15

Y1 - 2010/4/15

N2 - 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.

AB - 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.

KW - Animals

KW - Cell Polarity

KW - Cells, Cultured

KW - Forkhead Transcription Factors

KW - Gene Expression Regulation, Developmental

KW - Gene Knockdown Techniques

KW - Hippocampus

KW - Neurons

KW - RNA Interference

KW - Rats

KW - p21-Activated Kinases

KW - Journal Article

KW - Research Support, N.I.H., Extramural

KW - Research Support, Non-U.S. Gov't

U2 - 10.1101/gad.1880510

DO - 10.1101/gad.1880510

M3 - SCORING: Journal article

C2 - 20395366

VL - 24

SP - 799

EP - 813

JO - GENE DEV

JF - GENE DEV

SN - 0890-9369

IS - 8

ER -