Cytoplasmic Dynein (<i>ddlc1</i>) Mutations Cause Morphogenetic Defects and Apoptotic Cell Death in <i>Drosophila melanogaster</i>

Dick, Thomas; Ray, Krishanu; Salz, Helen K.; Chia, William

doi:10.1128/mcb.16.5.1966

Cited by 162 publications

(175 citation statements)

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“…Ectopic caspase activity was previously shown to be present in Drosophila ddlc1 mutants (23), and Ddlc1 inhibits the proapoptotic activity of Bim in mammalian cells (21). As caspases are required to complete salivary gland cell degradation (14,18,19), we hypothesized that ddlc1 may regulate caspases in salivary glands.…”

Section: Resultsmentioning

confidence: 99%

“…Dynein light chain encodes an 8-kD protein that binds to a variety of cargo and is highly conserved from Chlamydomonas to humans (22). In Drosophila, Ddlc1 is cytoplasmic and ubiquitously expressed, and complete loss of function of ddlc1 causes embryonic lethality and ectopic apoptosis (23). Partial loss of function mutations in Drosophila ddlc1 cause female sterility, alter sensory neuron development, and cause defects in axon guidance (24).…”

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confidence: 99%

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Dynein light chain 1 is required for autophagy, protein clearance, and cell death inDrosophila

Batlevi

Martin

Pandey

et al. 2009

Proc. Natl. Acad. Sci. U.S.A.

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Autophagy is a catabolic pathway that is important for turnover of long-lived proteins and organelles, and has been implicated in cell survival, tumor progression, protection from infection, neurodegeneration, and cell death. Autophagy and caspases are required for type II autophagic cell death of Drosophila larval salivary glands during development, but the mechanisms that regulate these degradation pathways are not understood. We conducted a forward genetic screen for genes that are required for salivary gland cell death, and here we describe the identification of Drosophila dynein light chain 1 (ddlc1) as a gene that is required for type II cell death. Autophagy is attenuated in ddlc1 mutants, but caspases are active in these cells. ddlc1 mutant salivary glands develop large fibrillar protein inclusions that stain positive for amyloid-specific dyes and ubiquitin. Ectopic expression of Atg1 is sufficient to induce autophagy, clear protein inclusions, and rescue degradation of ddlc1 mutant salivary glands. Furthermore, ddlc1 mutant larvae have decreased motility, and mutations in ddlc1 enhance the impairment of motility that is observed in a Drosophila model of neurodegenerative disease. Significantly, this decrease in larval motility is associated with decreased clearance of protein with polyglutamine expansion, the accumulation of p62 in neurons and muscles, and fewer synaptic boutons. These results indicate that DDLC1 is required for protein clearance by autophagy that is associated with autophagic cell death and neurodegeneration.macroautophagy | protein degradation | neurodegeneration M acroautophagy (autophagy) is a conserved catabolic pathway (1). Autophagy involves the formation of autophagosomes around cytoplasmic components, and fusion with lysosomes enables degradation of autophagosome cargo. Studies of yeast identified Atg genes that are required for autophagy during starvation (2-4). Autophagy is also activated during starvation in animals (5), but the complexity of higher animals, and the association of autophagy with diseases and cell death, raises questions about how autophagy is regulated and cargo is recruited and delivered to lysosomes in multicellular organisms.The role of autophagy in programmed cell death has been a subject of debate (6). Autophagy has a well established role in cell survival, and decreased Atg gene function can promote cell death (7). There is also evidence that autophagy plays a protective role against neurodegeneration in the setting of disease (8, 9), as well as under basal conditions (10, 11). Autophagosomes have been associated with dying cells during development (12, 13), and recent studies indicate that autophagy can promote the degradation and clearance of cells during cell death (14-17). This apparent paradoxical role of autophagy in both cell survival and death raises questions about how autophagy is regulated and influences different cell fates.Drosophila larval salivary glands possess type II cell death morphology during development, and contain numerous autop...

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Section: Resultsmentioning

confidence: 99%

mentioning

confidence: 99%

Dynein light chain 1 is required for autophagy, protein clearance, and cell death inDrosophila

Batlevi

Martin

Pandey

et al. 2009

Proc. Natl. Acad. Sci. U.S.A.

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“…Therefore, in view of these functions, this gene fulfills the criteria of a house-keeping gene whose down-regulated expression could induce lethality. This assumption was further reinforced by the fact that loss of function of the dynein light chain has been reported to cause widespread apoptotic cell death in Drosophila melanogaster (Dick et al, 1996). Experiments with antisense oligonucleotides could help to clarify the effect of a decrease in dynein activity on cell viability.…”

Section: Osteonectin/sparc and Dynein Heavy Chain/map 1c Genesmentioning

confidence: 90%

Differentially expressed genes in C6.9 glioma cells during vitamin D-induced cell death program

et al. 1998

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C6.9 rat glioma cells undergo a cell death program when exposed to 1,25-dihydroxyvitamin D3 (1,25-D3). As a global analytical approach, we have investigated gene expression in C6.9 engaged in this cell death program using differential screening of a rat brain cDNA library with probes derived from control and 1,25-D3-treated cells. Using this methodology we report the isolation of 61 differentially expressed cDNAs. Forty-seven cDNAs correspond to genes already characterized in rat cells or tissues. Seven cDNAs are homologous to yeast, mouse or human genes and seven are not related to known genes. Some of the characterized genes have been reported to be differentially expressed following induction of programmed cell death. These include PMP22/gas3, MGP and b-tubulin. For the first time, we also show a cell death program induced up-regulation of the c-myc associated primary response gene CRP, and of the proteasome RN3 subunit and TCTP/mortalin genes. Another interesting feature of this 1,25-D3 induced-cell death program is the down-regulated expression of transcripts for the microtubule motor dynein heavy chain/MAP 1C and of the calcium-binding S100b protein. Finally 15 upregulated cDNAs encode ribosomal proteins suggesting a possible involvement of the translational apparatus in this cell program. Alternatively, these ribosomal protein genes could be up-regulated in response to altered rates of cellular metabolism, as has been demonstrated for most of the other isolated genes which encode proteins involved in metabolic pathways. Thus, this study presents to our knowledge the first characterization of genes which are differentially expressed during a cell death program induced by 1,25-D3. Therefore, this data provides new information on the fundamental mechanisms which participate in the antineoplastic effects of 1,25-D3 and on the machinery of a cell death program in a glioma cell line.

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“…The staining was also found along the F-actin assembly in progressed investment cones (arrows, Figure 2, C and D), but it was always excluded from the leading edges of the cones (arrowheads, Figure 2, C and D). Identical staining along the progressed cones was observed with another DDLC1 specific antisera as well (Dick et al, 1996), and both the antisera recognized an approximately 10-kDa band in the adult head and abdomen extracts (unpublished data). Such enrichments along the F-actin cones were not visible in ddlc1 ins1 hemizygous testis, which contains significantly lower levels of Ddlc1 mRNA (Ghosh-Roy et al, 2004).…”

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confidence: 99%

“…The stained specimens were mounted under a coverslip using antifade mounting media (Vectashield, Vector Laboratories, Burlingame, CA). Mouse-anti-P10 (Dick et al, 1996) at 1/500 and rat-anti-DDLC1 at 1/200 (Ghosh-Roy et al, 2004) were used for the immunolocalization of DDLC1. The monoclonal anti-DHC (Sharp et al, 2000) and polyclonal anti-Shibire (Estes et al, 1996) were used at 1/10 and 1/200 dilutions, respectively.…”

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confidence: 99%

Dynein Light Chain 1 Regulates Dynamin-mediated F-Actin Assembly during Sperm Individualization inDrosophila

Ghosh-Roy

Desai

Ray

2005

MBoC

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Toward the end of spermiogenesis, spermatid nuclei are compacted and the clonally related spermatids individualize to become mature and active sperm. Studies in Drosophila showed that caudal end-directed movement of a microfilamentrich structure, called investment cone, expels the cytoplasmic contents of individual spermatids. F-actin dynamics plays an important role in this process. Here we report that the dynein light chain 1 (DLC1) of Drosophila is involved in two separate cellular processes during sperm individualization. It is enriched around spermatid nuclei during postelongation stages and plays an important role in the dynein-dynactin-dependent rostral retention of the nuclei during this period. In addition, DDLC1 colocalizes with dynamin along investment cones and regulates F-actin assembly at this organelle by retaining dynamin along the cones. Interestingly, we found that this process does not require the other subunits of cytoplasmic dynein-dynactin complex. Altogether, these observations suggest that DLC1 could independently regulate multiple cellular functions and established a novel role of this protein in F-actin assembly in Drosophila. INTRODUCTIONSperm elongation and maturation involves complex choreography of a range of different cytoskeletal events leading to a large-scale alteration of cell shape and bulk membrane movement. One of the unique features of sperm differentiation is the clearing of cytoplasmic contents of spermatids after elongation, which also separates them as individual sperm. It is a key step to form mature and active sperm. Morphogenetic changes associated with sperm individualization have been studied in detail in Drosophila (reviewed by Lindsley and Tokuyasu, 1980). It involves compaction of the nuclei, formation of the microfilament rich investment cones around the nucleus, and extrusion of cytoplasmic contents of each spermatid by a caudal end-directed movement of the investment cone. In comparison, the molecular mechanisms underlying these processes are not so well understood.F-actin and Lamin are the two known cytoskeleton components of investment cone, also known as F-actin cone (Fabrizio et al., 1998;Arama et al., 2003). Pharmacological treatments of isolated cysts established that F-actin dynamics plays a critical role in membrane extraction and F-actin cone movement and that both these processes are microtubule independent (Noguchi and Miller, 2003). F-actin-associated proteins, such as capping protein, cortactin, Arp2/3 complex, and myosin VI, are enriched at the leading edges of F-actin cones, whereas dynamin is localized throughout (Rogat and Miller, 2002), indicating that F-actin assembly would be initiated at the leading edges. Although, a later study showed that the F-actin assembly occurs throughout the cone (Noguchi and Miller, 2003). The F-actin cone bundles appeared disrupted in myosin VI homozygous testes (Hicks et al., 1999) and genetic interaction studies showed that myosin VI (jar 1 ) and dynamin (shi ts1 ) could act in parallel pathways to maintain t...

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Cytoplasmic Dynein (ddlc1) Mutations Cause Morphogenetic Defects and Apoptotic Cell Death in Drosophila melanogaster

Cited by 162 publications

References 43 publications

Dynein light chain 1 is required for autophagy, protein clearance, and cell death inDrosophila

Dynein light chain 1 is required for autophagy, protein clearance, and cell death inDrosophila

Differentially expressed genes in C6.9 glioma cells during vitamin D-induced cell death program

Dynein Light Chain 1 Regulates Dynamin-mediated F-Actin Assembly during Sperm Individualization inDrosophila

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