Autophagy regulates Notch degradation and modulates stem cell development and neurogenesis

Xiaoting Wu, Angeleen Fleming, Thomas Ricketts, Mariana Pavel, Herbert Virgin, Fiona M. Menzies & David C. Rubinsztein

 Nature Communications. 2016 Feb 03. doi: 10.1038/ncomms10533

Speaker: Tan Sia Seng (陳聲昇)                                   Time: 13:00~14:00, May. 13, 2016

Commentator: Li-Jin Hsu, Ph.D. (徐麗君教授)          Place: Room 601

Abstract:

Autophagy is an evolutionarily conserved physiology process that serves many functions including fusion with lysosomes to degrade unwanted substance in cells. The functions of the autophagy have been implicated in numerous diseases such as neurodegenerative conditions, metabolic diseases and cancers. An important role for autophagy in embryogenesis and development recently has been reported, as deletion of various ATG genes cause overt phenotypes or lethality in mice. Despite Notch, a master regulator of neural stem cells and neuronal development signaling pathway, involves in embryo development and that endocytosis is a pathway to degrade Notch1, the mechanism by which on the degradation of Notch by autophagy remains elusive. In this paper, the authors found that Notch1 can be degraded by autophagy independently since the plasma membrane ATG16L1-containing vesicles can traffic to autophagosomes as well as enter the autophagic pathway via its endocytic route. Mutation in ATG16L1 gene to generate a hypomorphy mouse demonstrates that this model is modestly impaired in its autophagic ability, which can influence early-state cell development in variant tissues. Notch1 is much more stable in primary neuron and brain neuronal development in hypomorphy mouse compared to wild-type mice, suggesting autophagy can modulate Notch1 degradation and contribute to the maturation of neuron indirectly. The delayed development phenomena are also observed in several tissues by flow cytometry, implying that Notch may affect stem cell development in certain tissues as well. In summary, the authors find that an impaired autophagic process can delay the development of stem cell and reveal modest changes in autophagic machinery can affect stem cell fate that may have relevance for diverse disease conditions.

References

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