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

• DOI: 10.1016/j.neuron.2018.08.017
• Publication Date: 2018-09-06T14:43:13Z
• Authors: Iris Schäffner; Georgia Minakaki; M. Amir Khan; Elli-Anna Balta; Ursula Schlötzer-...; Tobias J. Schwarz; Ruth Beckervorder...; Beate Winner; Ashley E. Webb; Ronald A. DePinho; Jihye Paik; Wolfgang Wurst; Jochen Klucken; D. Chichung Lie
• Keywords: Neurons; methods [Cell Separation]; physiology [Autophagy]; metabolism [Forkhead Transcription Factors]; Neurogenesis; Forkhead Transcription Factors; Mice, Transgenic; Cell Separation; physiology [Neurogenesis]; physiology [Morphogenesis]; Foxo ; Adult Neurogenesis ; Aging ; Autism ; Autophagy ; Hippocampus ; Spines ; Stem Cells; metabolism [Neurons]; Autophagy; Morphogenesis; Animals; ddc:610; Cells, Cultured

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.