A FOXO-Pak1 transcriptional pathway controls neuronal polarity
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A FOXO-Pak1 transcriptional pathway controls neuronal polarity. / de la Torre-Ubieta, Luis; Gaudillière, Brice; Yang, Yue; Ikeuchi, Yoshiho; Yamada, Tomoko; DiBacco, Sara; Stegmüller, Judith; Schüller, Ulrich; Salih, Dervis A; Rowitch, David H; Brunet, Anne; Bonni, Azad.
in: GENE DEV, Jahrgang 24, Nr. 8, 15.04.2010, S. 799-813.Publikationen: SCORING: Beitrag in Fachzeitschrift/Zeitung › SCORING: Zeitschriftenaufsatz › Forschung › Begutachtung
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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 -