Knockout of Atg5 delays the maturation and reduces the survival of adult-generated neurons in the hippocampus

Autophagy is an evolutionarily conserved lysosomal degradation pathway that plays important roles in cell maintenance, expansion and differentiation. Removal of genes essential for autophagy from embryonic neural stem and precursor cells reduces the survival and inhibits neuronal differentiation of...

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Published in:	Cell death & disease Vol. 7; no. 3; p. e2127
Main Authors:	Xi, Y, Dhaliwal, J S, Ceizar, M, Vaculik, M, Kumar, K L, Lagace, D C
Format:	Journal Article
Language:	English
Published:	London Nature Publishing Group UK 03-03-2016 Springer Nature B.V Nature Publishing Group
Subjects:	14/19 631/378/1595/1554 631/378/2571/2579 631/378/368/2431 631/80/82/39 64/110 64/60 82/51 Adult Stem Cells - cytology Adult Stem Cells - metabolism Animals Antibodies Autophagy Autophagy - physiology Autophagy-Related Protein 5 bcl-2-Associated X Protein - genetics bcl-2-Associated X Protein - metabolism Biochemistry Biomedical and Life Sciences Brain Cell Biology Cell Culture Cell Survival - physiology Gene Knockdown Techniques Hippocampus - cytology Hippocampus - metabolism Immunology Life Sciences Mice Mice, Knockout Microtubule-Associated Proteins - genetics Microtubule-Associated Proteins - metabolism Neural Stem Cells - cytology Neural Stem Cells - metabolism Neurogenesis - physiology Neurons Neurons - cytology Neurons - metabolism Original original-article Protein expression Signal transduction
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Summary:	Autophagy is an evolutionarily conserved lysosomal degradation pathway that plays important roles in cell maintenance, expansion and differentiation. Removal of genes essential for autophagy from embryonic neural stem and precursor cells reduces the survival and inhibits neuronal differentiation of adult-generated neurons. No study has modified autophagy within the adult precursor cells, leaving the cell-autonomous role of autophagy in adult neurogenesis unknown. Here we demonstrate that autophagic flux exists in the adult dividing progenitor cells and their progeny in the dentate gyrus. To investigate the role of autophagy in adult hippocampal neurogenesis, we genetically deleted Autophagy-related gene 5 ( Atg5 ) that reduced autophagic flux and the survival of the progeny of dividing progenitor cells. This significant reduction in survival of adult-generated neurons is accompanied by a delay in neuronal maturation, including a transient reduction in spine density in the absence of a change in differentiation. The delay in cell maturation and loss of progeny of the Atg5-null cells was not present in mice that lacked the essential pro-apoptotic protein Bax (Bcl-2-associated X protein), suggesting that Atg5-deficient cells die through a Bax-dependent mechanism. In addition, there was a loss of Atg5-null cells following exposure to running, suggesting that Atg5 is required for running-induced increases in neurogenesis. These findings highlight the cell-autonomous requirement of Atg5 in the survival of adult-generated neurons.
Bibliography:	ObjectType-Article-1 SourceType-Scholarly Journals-1 ObjectType-Feature-2 content type line 23 Both authors contributed equally for co-first authorship.
ISSN:	2041-4889 2041-4889
DOI:	10.1038/cddis.2015.406