Institute of Biochemistry, Friedrich-Alexander Universität Erlangen-Nürnberg, 91054 Erlangen, Germany; Department of Stem Cell Biology, Friedrich-Alexander-Universität Erlangen-Nürnberg, 91054 Erlangen, Germany.
Department of Molecular Neurology, University Hospital Erlangen, Friedrich-Alexander Universität Erlangen-Nürnberg, 91054 Erlangen, Germany.
Neuron. 2018 Sep 19;99(6):1188-1203.e6. doi: 10.1016/j.neuron.2018.08.017. Epub 2018 Sep 6.
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.
自噬是一种保守的分解代谢途径，在哺乳动物神经发育和人类神经发育性疾病中具有新的功能。控制神经元发育中自噬的机制尚未完全阐明。在这里，我们发现条件性敲除叉头框 O 转录因子 FoxO1、FoxO3 和 FoxO4 会严重损害成年小鼠海马体发育神经元中的自噬流。此外，FoxO 缺乏导致成年产生的神经元中树突形态改变、棘密度增加和棘突位置异常。引人注目的是，自噬的药理学诱导足以纠正 FoxO 缺陷神经元的异常树突和棘突发育。总的来说，这些发现揭示了 FoxO 转录因子、自噬流和发育中神经元成熟之间的新联系。
