Drosophila caspases involved in developmentally regulated programmed cell death of peptidergic neurons during early metamorphosis

Abstract

A great number of obsolete larval neurons in the Drosophila central nervous system are eliminated by developmentally programmed cell death (PCD) during early metamorphosis. To elucidate the mechanisms of neuronal PCD occurring during this period, we undertook genetic dissection of seven currently known Drosophila caspases in the PCD of a group of interneurons (vCrz) that produce corazonin (Crz) neuropeptide in the ventral nerve cord. The molecular death program in the vCrz neurons initiates within 1 hour after pupariation, as demonstrated by the cytological signs of cell death and caspase activation. PCD was significantly suppressed in dronc-null mutants, but not in null mutants of either dredd or strica. A double mutation lacking both dronc and strica impaired PCD phenotype more severely than did a dronc mutation alone, but comparably to a triple dredd/strica/dronc mutation, indicating that dronc is a main initiator caspase, while strica plays a minor role that overlaps with dronc's. As for effector caspases, vCrz PCD requires both ice and dcp-1 functions, as they work cooperatively for a timely removal of the vCrz neurons. Interestingly, the activation of the Ice and Dcp-1 is not solely dependent on Dronc and Strica, implying an alternative pathway to activate the effectors. Two remaining effector caspase genes, decay and damm, found no apparent functions in the neuronal PCD, at least during early metamorphosis. Overall, our work revealed that vCrz PCD utilizes dronc, strica, dcp-1, and ice wherein the activation of Ice and Dcp-1 requires a novel pathway in addition to the initiator caspases.

Ecdysone-mediated programmed cell death in Drosophila

“…Strica has some level of redundancy with Dronc during PCD in the ovary and a subset of neurons that secrete the neuropeptide Corazanin (vCrz) (Baum et al, 2007, Lee et al, 2011. Along with Drice, Decay is responsible for high levels of caspase activity present in the larval midgut during PCD although its function here is unknown (Denton et al, 2009).…”

Apoptotic mechanisms during competition of ribosomal protein mutant cells: roles of the initiator caspases Dronc and Dream/Strica

“…Dream/ strica and Dronc are also required redundantly for nurse cell death during oogenesis and the programmed elimination of certain peptidergic neurons from the CNS during pupariation. 53,59 Further characterization of mechanisms of Dream/Strica activation may be revealing concerning the induction of competitive apoptosis by interactions between wild-type and Rp/+ cells.…”

Subtype-specific neuronal remodeling duringDrosophilametamorphosis

“…32 In all three cases, the timed activation of PCD is mediated by caspases and the pro-apoptotic gene reaper (and in the case of type II neurons also grim) in a highly subtype-specific manner. 11,12,31,32 Work in vCrz neurons, which die shortly after pupariation, demonstrates that ecdyone signaling induces subtypespecific expression of reaper, the initiator caspases dronc and strica as well as the effector caspases dcp-1 and ice. 31 How is metamorphic neuronal PCD triggered in only specific neuronal subsets?…”

“…11,12,31,32 Work in vCrz neurons, which die shortly after pupariation, demonstrates that ecdyone signaling induces subtypespecific expression of reaper, the initiator caspases dronc and strica as well as the effector caspases dcp-1 and ice. 31 How is metamorphic neuronal PCD triggered in only specific neuronal subsets? The regulatory steps between ecdysone signaling and cell death gene expression in neurons are poorly defined.…”