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Neuron. 2018 Sep 19;99(6):1188-1203.e6. doi: 10.1016/j.neuron.2018.08.017. Epub 2018 Sep 6.

FoxO Function Is Essential for Maintenance of Autophagic Flux and Neuronal Morphogenesis in Adult Neurogenesis.

Author information

1
Institute of Biochemistry, Friedrich-Alexander Universität Erlangen-Nürnberg, 91054 Erlangen, Germany; Department of Stem Cell Biology, Friedrich-Alexander-Universität Erlangen-Nürnberg, 91054 Erlangen, Germany.
2
Department of Molecular Neurology, University Hospital Erlangen, Friedrich-Alexander Universität Erlangen-Nürnberg, 91054 Erlangen, Germany.
3
Institute of Developmental Genetics, Helmholtz Zentrum München, Technische Universität München-Weihenstephan, 85764 Neuherberg/Munich, Germany.
4
Institute of Biochemistry, Friedrich-Alexander Universität Erlangen-Nürnberg, 91054 Erlangen, Germany.
5
Department of Ophthalmology, University Hospital Erlangen, Friedrich-Alexander-Universität Erlangen-Nürnberg, 91054 Erlangen, Germany.
6
Department of Stem Cell Biology, Friedrich-Alexander-Universität Erlangen-Nürnberg, 91054 Erlangen, Germany.
7
Department of Molecular Biology, Cell Biology and Biochemistry, Brown University, Providence, RI 02903, USA.
8
Department of Cancer Biology, The University of Texas MD Anderson Cancer Center, Houston, TX 77054, USA.
9
Department of Pathology and Laboratory Medicine, Weill Cornell Medicine, New York, NY 10065, USA.
10
Institute of Developmental Genetics, Helmholtz Zentrum München, Technische Universität München-Weihenstephan, 85764 Neuherberg/Munich, Germany; German Center for Neurodegenerative Diseases (DZNE), Site Munich, Munich Cluster for Systems Neurology (SyNergy), 81377 Munich, Germany.
11
Institute of Biochemistry, Friedrich-Alexander Universität Erlangen-Nürnberg, 91054 Erlangen, Germany. Electronic address: chi.lie@fau.de.

Abstract

Autophagy is a conserved catabolic pathway with emerging functions in mammalian neurodevelopment and human neurodevelopmental diseases. The mechanisms controlling autophagy in neuronal development are not fully understood. Here, we found that conditional deletion of the Forkhead Box O transcription factors FoxO1, FoxO3, and FoxO4 strongly impaired autophagic flux in developing neurons of the adult mouse hippocampus. Moreover, FoxO deficiency led to altered dendritic morphology, increased spine density, and aberrant spine positioning in adult-generated neurons. Strikingly, pharmacological induction of autophagy was sufficient to correct abnormal dendrite and spine development of FoxO-deficient neurons. Collectively, these findings reveal a novel link between FoxO transcription factors, autophagic flux, and maturation of developing neurons.

KEYWORDS:

FoxO; adult neurogenesis; aging; autism; autophagy; hippocampus; spines; stem cells

PMID:
30197237
PMCID:
PMC6186958
[Available on 2019-09-19]
DOI:
10.1016/j.neuron.2018.08.017

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