How autophagy is related to programmed cell death during the development of the nervous system

Boya, Patricia; Mellén, M A; Rosa, Enrique J. de la

doi:10.1042/bst0360813

Cited by 37 publications

(31 citation statements)

References 44 publications

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“…Cell death associated with neurogenesis in the DT region of the E4 and E5 retina seems to require autophagy (reviewed in ref. 17), whereas morphogenetic cell death in the ON region, as well as later neurotrophic cell death, does not.…”

Section: Resultsmentioning

confidence: 91%

“…13,14 Recent studies have revealed a homeostatic role of autophagy with respect to apoptosis and the clearance of dead cells associated, at least, with cavitation in mouse embryoid bodies and chick retinal development. [15][16][17] In these studies, the genetic inhibition of autophagy, by using knockout mice of Atg genes, as well as its pharmacological inhibition, by 3-methyl-adenine (3-MA), prevented PS presentation and the subsequent phagocytosis of apoptotic bodies.…”

Section: Introductionmentioning

confidence: 99%

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Autophagy is not universally required for phosphatidyl-serine exposure and apoptotic cell engulfment during neural development

Mellén¹,

Rosa²,

Boya³

2009

Autophagy

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Apoptosis and autophagy are physiological processes implicated in the maintenance of cell and tissue homeostasis. We took advantage of the existence of multiple phases of developmental cell death in the embryonic chick retina and of the availability of short-term organotypic retinal cultures to explore the possible relationship between apoptosis and autophagy during neural development. We examined retinas at embryonic day 5, an early stage at which cell death is related to eye morphogenesis and to retinal ganglion cell generation, as well as at embryonic day 9, when cell death is associated with neurotrophic support of the retinal ganglion cells. Exposure to 3-methyl-adenine, a classical inhibitor of autophagy, elicited a selective accumulation of apoptotic bodies in the dorsotemporal area of embryonic day 5 retinas where neurogenesis is taking place. This accumulation was correlated with a blockage of phosphatidyl-serine presentation and, consequently, with a lack of engulfment of the dying cells by their neighbors. In striking contrast, none of these phenomena were observed in association with cell death in the optic nerve and optic fissure at embryonic day 5, or in embryonic day 9 retinas. Our data suggest that autophagy is essential for phosphatidyl-serine presentation by apoptotic cells during the phase of cell death associated to neurogenesis, but this is not a universal requirement for all phases of cell death occurring during retinal development.

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Section: Resultsmentioning

confidence: 91%

Section: Introductionmentioning

confidence: 99%

Autophagy is not universally required for phosphatidyl-serine exposure and apoptotic cell engulfment during neural development

Mellén¹,

Rosa²,

Boya³

2009

Autophagy

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“…LysoTracker has also been a useful tool for assessing autophagy [23][24][25][26] and in response to serum starvation, differentiated ES cells display a marked increase in the number of LysoTracker staining puncta (compare Figure 2D with 2A). This likely indicates an increase in the formation of autophagolysosomes and lysosomes in response to decreased nutrient availability (as has been shown in other contexts using LysoTracker 24,25 ).…”

Section: Discussionmentioning

confidence: 99%

Use of LysoTracker to Detect Programmed Cell Death in Embryos and Differentiating Embryonic Stem Cells

Fogel

Thein

Mariani

2012

JoVE

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Programmed cell death (PCD) occurs in adults to maintain normal tissue homeostasis and during embryological development to shape tissues and organs 1,2,6,7 . During development, toxic chemicals or genetic alterations can cause an increase in PCD or change PCD patterns resulting in developmental abnormalities and birth defects [3][4][5] . To understand the etiology of these defects, the study of embryos can be complemented with in vitro assays that use differentiating embryonic stem (ES) cells.Apoptosis is a well-studied form of PCD that involves both intrinsic and extrinsic signaling to activate the caspase enzyme cascade. Characteristic cell changes include membrane blebbing, nuclear shrinking, and DNA fragmentation. Other forms of PCD do not involve caspase activation and may be the end-result of prolonged autophagy. Regardless of the PCD pathway, dying cells need to be removed. In adults, the immune cells perform this function, while in embryos, where the immune system has not yet developed, removal occurs by an alternative mechanism. This mechanism involves neighboring cells (called "non-professional phagocytes") taking on a phagocytic role-they recognize the 'eat me' signal on the surface of the dying cell and engulf it [8][9][10] . After engulfment, the debris is brought to the lysosome for degradation. Thus regardless of PCD mechanism, an increase in lysosomal activity can be correlated with increased cell death.To study PCD, a simple assay to visualize lysosomes in thick tissues and multilayer differentiating cultures can be useful. LysoTracker dye is a highly soluble small molecule that is retained in acidic subcellular compartments such as the lysosome [11][12][13] . The dye is taken up by diffusion and through the circulation. Since penetration is not a hindrance, visualization of PCD in thick tissues and multi-layer cultures is possible 12,13 . In contrast, TUNEL (Terminal deoxynucleotidyl transferase dUTP nick end labeling) analysis 14 , is limited to small samples, histological sections, and monolayer cultures because the procedure requires the entry/permeability of a terminal transferase.In contrast to Aniline blue, which diffuses and is dissolved by solvents, LysoTracker Red DND-99 is fixable, bright, and stable. Staining can be visualized with standard fluorescent or confocal microscopy in whole-mount or section using aqueous or solvent-based mounting media 12,13 . Here we describe protocols using this dye to look at PCD in normal and sonic hedgehog null mouse embryos. In addition, we demonstrate analysis of PCD in differentiating ES cell cultures and present a simple quantification method. In summary, LysoTracker staining can be a great complement to other methods of detecting PCD. Video LinkThe video component of this article can be found at

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“…ATP in turn delivers energy for the removal of apoptotic cells through engulfment and subsequent degradation. In the mature CNS, mechanical or biochemical insults of neurons are often accompanied by autophagy, which is thought to promote regenerative events or cell destruction, depending on the spatial-temporal context (Boya et al, 2008).…”

Section: Discussionmentioning

confidence: 99%

Antidepressant Drugs Diversely Affect Autophagy Pathways in Astrocytes and Neurons—Dissociation from Cholesterol Homeostasis

Zschocke

Zimmermann

Berning

et al. 2011

Neuropsychopharmacol

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In the search for antidepressants' (ADs') mechanisms of action beyond their influence on monoaminergic neurotransmission, we analyzed the effects of three structurally and pharmacologically different ADs on autophagic processes in rat primary astrocytes and neurons. Autophagy has a significant role in controlling protein turnover and energy supply. Both, the tricyclic AD amitriptyline (AMI) and the selective serotonin re-uptake inhibitor citalopram (CIT) induced autophagy as mirrored by pronounced upregulation and cellular redistribution of the marker LC3B-II. Redistribution was characterized by formation of LC3B-II-positive structures indicative of autophagosomes, which associated with AVs in a time-dependent manner. Deletion of Atg5, representing a central mediator of autophagy in MEFs, led to abrogation of AMI-induced LC3B-I/II conversion. By contrast, VEN, a selective serotonin and noradrenaline reuptake inhibitor, did not promote autophagic processes in either cell type. The stimulatory impact of AMI on autophagy partly involved class-III PI3 kinase-dependent pathways as 3-methyladenine slightly diminished the effects of AMI. Autophagic flux as defined by autophagosome turnover was vastly undisturbed, and degradation of long-lived proteins was augmented upon AMI treatment. Enhanced autophagy was dissociated from drug-induced alterations in cholesterol homeostasis. Subsequent to AMI-and CIT-mediated autophagy induction, neuronal and glial viability decreased, with neurons showing signs of apoptosis. In conclusion, we report that distinct ADs promote autophagy in neural cells, with important implications on energy homeostasis.

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How autophagy is related to programmed cell death during the development of the nervous system

Cited by 37 publications

References 44 publications

Autophagy is not universally required for phosphatidyl-serine exposure and apoptotic cell engulfment during neural development

Autophagy is not universally required for phosphatidyl-serine exposure and apoptotic cell engulfment during neural development

Use of LysoTracker to Detect Programmed Cell Death in Embryos and Differentiating Embryonic Stem Cells

Antidepressant Drugs Diversely Affect Autophagy Pathways in Astrocytes and Neurons—Dissociation from Cholesterol Homeostasis

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