Bcl-2 proteins and autophagy regulate mitochondrial dynamics during programmed cell death in the<i>Drosophila</i>ovary

Tanner, E; Blute, Todd A.; Brachmann, Carrie Baker; McCall, Kimberly

doi:10.1242/dev.057943

Cited by 71 publications

(61 citation statements)

References 48 publications

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“…Recently, we have determined that mitochondrial events and the Bcl-2 family partially control PCD in mid oogenesis. 10 However, how nutritional cues link to Dcp-1, DIAP1, or mitochondria has not been determined. One candidate for the regulation of starvation-induced PCD in the ovary is the insulin signaling pathway.…”

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Role of the insulin/Tor signaling network in starvation-induced programmed cell death in Drosophila oogenesis

Pritchett

McCall

2012

Cell Death Differ

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Amino-acid starvation leads to an inhibition of cellular proliferation and the induction of programmed cell death (PCD) in the Drosophila ovary. Disruption of insulin signaling has been shown to inhibit the progression of oogenesis, but it is unclear whether this phenotype mimics starvation. Here, we investigate whether the insulin-mediated phosphoinositide kinase-3 pathway regulates PCD in mid oogenesis. We reasoned that under well-fed conditions, disruption of positive components of the insulin signaling pathway within the germline would mimic starvation and produce degenerating egg chambers. Surprisingly, mutants did not mimic starvation but instead produced many abnormal egg chambers in which the somatic follicle cells disappeared and the germline persisted. These abnormal egg chambers did not show an induction of caspases and lysosomes like that observed in wild-type (WT) degenerating egg chambers. Egg chambers from insulin signaling mutants were resistant to starvation-induced PCD, indicating that a complete block in insulin-signaling prevents the proper response to starvation. However, target of rapamycin (Tor) mutants did show a phenotype that mimicked WT starvation-induced PCD, indicating an insulin independent regulation of PCD via Tor signaling. These results suggest that inhibition of the insulin signaling pathway is not sufficient to regulate starvation-induced PCD in mid oogenesis. Furthermore, starvation-induced PCD is regulated by Tor signaling converging with the canonical insulin signaling pathway. The insulin-mediated class I phosphoinositide kinase-3 (PI3K) pathway is a highly conserved nutrient-sensing pathway in diverse organisms. In mammals, insulin signaling affects oocyte maturation and fertilization. 1,2 Mutations in the insulin signaling pathway in C. elegans can lengthen life span but reduce fertility. 3,4 Improper insulin signaling in Drosophila leads to reduced body size and female sterility. 5 Thus, insulin signaling is essential for reproduction in diverse organisms, but how this pathway regulates fertility is not fully understood.Proper nutrition during Drosophila oogenesis is critical for egg chamber production. 6-8 Depriving flies of yeast as a protein source leads to programmed cell death (PCD) at two stages: early oogenesis in the germarium and mid oogenesis during stages 7-9. 7 Egg chambers undergoing PCD during mid oogenesis are characterized by nuclear condensation and fragmentation of germline-derived nurse cells (NCs), engulfment by somatic follicle cells (FCs), and ultimately FC death. 5 During PCD in mid oogenesis, dying NCs show characteristics of both apoptotic and autophagic PCD. 5 The effector caspase Death caspase-1 (Dcp-1) is essential for germline PCD in mid oogenesis. dcp-1 mutants that have been starved display mid-stage egg chambers that have a persistence of uncondensed NC nuclei but an absence of FCs. 5 This phenotype indicates that the dcp-1 mutant germline is unable to die in response to starvation, although the FCs respond and undergo PCD. dcp-1 mutants ...

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confidence: 99%

Role of the insulin/Tor signaling network in starvation-induced programmed cell death in Drosophila oogenesis

Pritchett

McCall

2012

Cell Death Differ

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“…En effet, l'expression de debcl, supposé pro-apoptotique, protège en fait les neurones de la toxicité des protéines à polyglutamines, et, inversement, celle de buffy, qui serait anti-apoptotique, favorise cette dégénérescence neuronale [18]. Debcl et Buffy ne sont pas essentiels à la plupart des morts cellulaires développementales [19], leur rôle est restreint à certains tissus et à certains stades de développement [20]. En revanche, ils jouent un rôle important dans la mort cellulaire induite par un stress.…”

Section: Mort Cellulaireunclassified

“…En revanche, l'expression de buffy supprime les changements mitochondriaux associés à l'apoptose induite par la perte de fonction de pink1 [32], un gène codant une kinase mitochondriale dont la perte de fonction, chez l'homme, est associée à la maladie de Parkinson. Buffy et Debcl sont, par ailleurs, requis pour la mort des cellules nourricières au cours de l'ovogenèse où la perte de fonction de debcl ou de buffy conduit à une élongation du réseau mitochondrial [20]. Chez la drosophile, un lien existe entre les membres de la famille Bcl-2, la dynamique mitochondriale et la mort cellulaire.…”

Section: Mort Cellulaireunclassified

“…En effet, la surexpression de buffy inhibe la mort induite par Debcl [14] et des expériences de coexpression de buffy et debcl indiquent que Buffy doit inactiver Debcl pour pouvoir induire la dégénérescence des neurones en réponse aux protéines à polyglutamines [18]. Toutefois, buffy et debcl peuvent, dans de rares cas, coopérer pour induire la mort cellulaire [20]. Bien que cela n'ait pas été aujourd'hui mis en évidence, il est envisageable que des modifications post-traductionnelles, telles que celles qui ont été décrites pour Bcl-2 chez les mammifères, puissent contrôler les activités pro-ou anti-apoptotiques de Debcl et Buffy.…”

Section: Mort Cellulaireunclassified

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Lecome-backde la mitochondrie dans l’apoptose chez la drosophile

Clavier¹,

Rincheval-Arnold²,

Mignotte³

et al. 2016

Med Sci (Paris)

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“…Homologues of Bcl-2 family member in Drosophila melanogaster are limited to the anti-apoptotic Buffy and the pro-apoptotic Debcl (Quinn et al, 2003). In previous studies, overexpression of Buffy has been shown to confer survival advantages in response to external stimuli and under conditions of stress (Sevrioukov et al, 2007;Tanner et al, 2011;Monserrate et al, 2012;M'Angale and Staveley, 2016d). A role for this gene in the mitochondrial pathway has been described during Drosophila oogenesis (Tanner et al, 2011).…”

Section: Introductionmentioning

confidence: 99%

Knockdown of the putative Lifeguard homologue CG3814 in neurons of Drosophila melanogaster

M’Angale

Staveley

2016

Genet. Mol. Res.

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ABSTRACT.Lifeguard is an integral transmembrane protein that modulates FasL-mediated apoptosis by interfering with the activation of caspase 8. It is evolutionarily conserved, with homologues present in plants, nematodes, zebra fish, frog, chicken, mouse, monkey, and human. The Lifeguard homologue in Drosophila, CG3814, contains the Bax inhibitor-1 family motif of unknown function. Downregulation of Lifeguard disrupts cellular homeostasis and disease by sensitizing neurons to FasL-mediated apoptosis. We used bioinformatic analyses to identify CG3814, a putative homologue of Lifeguard, and knocked down CG3814/LFG expression under the control of the Dopa decarboxylase (Ddc-Gal4) transgene in Drosophila melanogaster neurons to investigate whether it possesses neuroprotective activity. Knockdown of CG3814/LFG in Ddc-Gal4-expressing neurons resulted in a shortened lifespan and impaired locomotor ability, phenotypes that are strongly associated with the degeneration and loss of dopaminergic neurons. Lifeguard interacts with anti-apoptotic Bcl-2 proteins and possibly pro-apoptotic proteins to exert its neuroprotective function. The co-expression of Buffy, the sole anti-apoptotic Bcl-2 gene family member in Drosophila, and CG3814/LFG by stable inducible RNA interference, suppresses the shortened lifespan and the premature agedependent loss in climbing ability. Suppression of CG3814/LFG in the Drosophila eye reduces the number of ommatidia and increases disruption of the ommatidial array. Overexpression of Buffy, along with the knockdown of CG3814/LFG, counteracts the eye phenotypes. Knockdown of CG3814/LFG in Ddc-Gal4-expressing neurons in Drosophila diminishes its neuroprotective ability and results in a shortened lifespan and loss of climbing ability, phenotypes that are improved upon overexpression of the pro-survival Buffy.

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Bcl-2 proteins and autophagy regulate mitochondrial dynamics during programmed cell death in theDrosophilaovary

Cited by 71 publications

References 48 publications

Role of the insulin/Tor signaling network in starvation-induced programmed cell death in Drosophila oogenesis

Role of the insulin/Tor signaling network in starvation-induced programmed cell death in Drosophila oogenesis

Lecome-backde la mitochondrie dans l’apoptose chez la drosophile

Knockdown of the putative Lifeguard homologue CG3814 in neurons of Drosophila melanogaster

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