Atg5 and Ambra1 differentially modulate neurogenesis in neural stem cells.

Patricia Vázquez, Ana I. Arroba, Francesco Cecconi, Enrique J. de la Rosa, Patricia Boya, Flora de Pablo

Research output: Contribution to journalArticle

Abstract

Neuroepithelial cells undergoing differentiation efficiently remodel their cytoskeleton and shape in an energy-consuming process. The capacity of autophagy to recycle cellular components and provide energy could fulfill these requirements, thus supporting differentiation. However, little is known regarding the role of basal autophagy in neural differentiation. Here we report an increase in the expression of the autophagy genes Atg7, Becn1, Ambra1 and LC3 in vivo in the mouse embryonic olfactory bulb (OB) during the initial period of neuronal differentiation at E15.5, along with a parallel increase in neuronal markers. In addition, we observed an increase in LC3 lipidation and autophagic flux during neuronal differentiation in cultured OB-derived stem/progenitor cells. Pharmacological inhibition of autophagy with 3-MA or wortmannin markedly decreased neurogenesis. These observations were supported by similar findings in two autophagy-deficient genetic models. In Ambra1 loss-of-function homozygous mice (gt/gt) the expression of several neural markers was decreased in the OB at E13.5 in vivo. In vitro, Ambra1 haploinsufficient cells developed as small neurospheres with an impaired capacity for neuronal generation. The addition of methylpyruvate during stem/progenitor cell differentiation in culture largely reversed the inhibition of neurogenesis induced by either 3-MA or Ambra1 haploinsufficiency, suggesting that neural stem/progenitor cells activate autophagy to fulfill their high energy demands. Further supporting the role of autophagy for neuronal differentiation Atg5-null OB cells differentiating in culture displayed decreased TuJ1 levels and lower number of cells with neurites. These results reveal new roles for autophagy-related molecules Atg5 and Ambra1 during early neuronal differentiation of stem/progenitor cells.

Original languageEnglish
Pages (from-to)187-199
Number of pages13
JournalAutophagy
Volume8
Issue number2
Publication statusPublished - Feb 1 2012

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Neural Stem Cells
Neurogenesis
Autophagy
Stem Cells
Olfactory Bulb
Cell Differentiation
Neuroepithelial Cells
Haploinsufficiency
Genetic Models
Neurites
Cytoskeleton
Cell Count
Pharmacology
Gene Expression

ASJC Scopus subject areas

  • Cell Biology
  • Molecular Biology

Cite this

Vázquez, P., Arroba, A. I., Cecconi, F., de la Rosa, E. J., Boya, P., & de Pablo, F. (2012). Atg5 and Ambra1 differentially modulate neurogenesis in neural stem cells. Autophagy, 8(2), 187-199.

Atg5 and Ambra1 differentially modulate neurogenesis in neural stem cells. / Vázquez, Patricia; Arroba, Ana I.; Cecconi, Francesco; de la Rosa, Enrique J.; Boya, Patricia; de Pablo, Flora.

In: Autophagy, Vol. 8, No. 2, 01.02.2012, p. 187-199.

Research output: Contribution to journalArticle

Vázquez, P, Arroba, AI, Cecconi, F, de la Rosa, EJ, Boya, P & de Pablo, F 2012, 'Atg5 and Ambra1 differentially modulate neurogenesis in neural stem cells.', Autophagy, vol. 8, no. 2, pp. 187-199.
Vázquez P, Arroba AI, Cecconi F, de la Rosa EJ, Boya P, de Pablo F. Atg5 and Ambra1 differentially modulate neurogenesis in neural stem cells. Autophagy. 2012 Feb 1;8(2):187-199.
Vázquez, Patricia ; Arroba, Ana I. ; Cecconi, Francesco ; de la Rosa, Enrique J. ; Boya, Patricia ; de Pablo, Flora. / Atg5 and Ambra1 differentially modulate neurogenesis in neural stem cells. In: Autophagy. 2012 ; Vol. 8, No. 2. pp. 187-199.
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