Mutations in the Novel Membrane Protein Spinster Interfere with Programmed Cell Death and Cause Neural Degeneration in<i>Drosophila melanogaster</i>

Nakano, Yoshiro; Fujitani, Kazuko; Kurihara, Joyce; Ragan, Janet; Usui-Aoki, Kazue; Shimoda, Lori M. N.; Lukácsovich, Tamás; Suzuki, Keiko; Sezaki, Mariko; Sano, Yumiko; Ueda, Ryo; Awano, Wakae; Kaneda, Mizuho; Umeda, Masato; Yamamoto, Daisuke

doi:10.1128/mcb.21.11.3775-3788.2001

Cited by 127 publications

(177 citation statements)

References 47 publications

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“…30 Persisting st14 nuclei have also been reported in mutants lacking the transmembrane protein Spinster. 31 Cell death induced by the human ortholog to Spinster, Hspin1, appears to include the formation of autophagic vacuoles. 32 While autophagic vacuoles have been reported previously in nurse cells, 33 a recent study using GFP fusion proteins failed to see any evidence of such vacuoles.…”

Section: Discussionmentioning

confidence: 99%

The Drosophila caspases Strica and Dronc function redundantly in programmed cell death during oogenesis

et al. 2007

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Programmed cell death (PCD) in the Drosophila ovary occurs either during mid-oogenesis, resulting in degeneration of the entire egg chamber or during late oogenesis, to facilitate the development of the oocyte. PCD during oogenesis is regulated by mechanisms different from those that control cell death in other Drosophila tissues. We have analyzed the role of caspases in PCD of the female germline by examining caspase mutants and overexpressing caspase inhibitors. Imprecise P-element excision was used to generate mutants of the initiator caspase strica. While null mutants of strica or another initiator caspase, dronc, display no ovary phenotype, we find that strica exhibits redundancy with dronc, during both mid-and late oogenesis. Ovaries of double mutants contain defective mid-stage egg chambers similar to those reported previously in dcp-1 mutants, and mature egg chambers with persisting nurse cell nuclei. In addition, the effector caspases drice and dcp-1 also display redundant functions during late oogenesis, resulting in persisting nurse cell nuclei. These findings indicate that caspases are required for nurse cell death during mid-oogenesis, and participate in developmental nurse cell death during late oogenesis. This reveals a novel pathway of cell death in the ovary that utilizes strica, dronc, dcp-1 and drice, and importantly illustrates strong redundancy among the caspases. The Drosophila caspases include three initiators with long prodomains -dronc (Drosophila Nedd-2-like caspase), dredd (Death-related ced-3/Nedd2-like) and strica, and four effectors -dcp-1 (death caspase-1), drice (Drosophila ice), damm and decay.

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Section: Discussionmentioning

confidence: 99%

The Drosophila caspases Strica and Dronc function redundantly in programmed cell death during oogenesis

et al. 2007

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“…Of them, Spns1 play roles in programmed cell death in Drosophila melanogaster and has orthologs in nematode, mouse, and human (39). Rabep2 is a RAB GTPase binding effector protein which encodes a member of AP-1 family of transcription factors involved in cell proliferation, differentiation, apoptosis, and other biological processes.…”

Section: Mouse Models Mouse Modelsmentioning

confidence: 99%

Genome-Wide Association and Fine Mapping of Genetic Loci Predisposing to Colon Carcinogenesis in Mice

Liu

Lü

Liu

et al. 2012

Molecular Cancer Research

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To identify the genetic determinants of colon tumorigenesis, 268 male mice from 33 inbred strains derived from different genealogies were treated with azoxymethane (AOM; 10 mg/kg) once a week for six weeks to induce colon tumors. Tumors were localized exclusively within the distal colon in each of the strains examined. Inbred mouse strains exhibit a large variability in genetic susceptibility to AOM-induced colon tumorigenesis. The mean colon tumor multiplicity ranged from 0 to 38.6 (mean ¼ 6.5 AE 8.6) and tumor volume ranged from 0 to 706.5 mm 3 (mean ¼ 87.4 AE 181.9) at 24 weeks after the first dose of AOM. AOM-induced colon tumor phenotypes are highly heritable in inbred mice, and 68.8% and 71.3% of total phenotypic variation in colon tumor multiplicity and tumor volume, respectively, are attributable to strain-dependent genetic background. Using 97,854 single-nucleotide polymorphisms, we carried out a genome-wide association study (GWAS) of AOM-induced colon tumorigenesis and identified a novel susceptibility locus on chromosome 15 (rs32359607, P ¼ 6.31 Â 10 -6 ). Subsequent fine mapping confirmed five (Scc3, Scc2, Scc12, Scc8, and Ccs1) of 16 linkage regions previously found to be associated with colon tumor susceptibility. These five loci were refined to less than 1 Mb genomic regions of interest. Major candidates in these loci are Sema5a, Fmn2, Grem2, Fap, Gsg1l, Xpo6, Rabep2, Eif3c, Unc5d, and Gpr65. In particular, the refined Scc3 locus shows high concordance with the human GWAS locus that underlies hereditary mixed polyposis syndrome. These findings increase our understanding of the complex genetics of colon tumorigenesis, and provide important insights into the pathways of colorectal cancer development and might ultimately lead to more effective individually targeted cancer prevention strategies. Mol Cancer Res; 10(1); 66-74. Ó2011 AACR.

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“…[7][8][9] Mutations in the corresponding genes results in aberrant autolysosome formation, leading to embryonic senescence and premature aging symptoms in Drosophila and zebrafish. 4,10 We recently have shown in zebrafish that Becn1/Beclin 1 suppression ameliorates developmental senescence and autolysosomal impairment associated with Spns1 deficiency, whereas loss of Tp53 exacerbates these characteristics in the Spns1-defective zebrafish embryos. 7 We also demonstrate that basal Tp53 activity has a certain protective role (s) against the Spns1 defect by suppressing autolysosome biogenesis and/or autophagosome-lysosome fusion.…”

Section: Introductionmentioning

confidence: 99%

Autolysosome biogenesis and developmental senescence are regulated by both Spns1 and v-ATPase

et al. 2016

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Spns1 (Spinster homolog 1 [Drosophila]) in vertebrates, as well as Spin (Spinster) in Drosophila, is a hypothetical lysosomal H C -carbohydrate transporter, which functions at a late stage of macroautophagy (hereafter autophagy). The Spin/Spns1 defect induces aberrant autolysosome formation that leads to developmental senescence in the embryonic stage and premature aging symptoms in adulthood. However, the molecular mechanism by which loss of Spin/Spns1 leads to the specific pathogenesis remains to be elucidated. Using chemical, genetic and CRISPR/Cas9-mediated genome-editing approaches in zebrafish, we investigated and determined a mechanism that suppresses embryonic senescence as well as autolysosomal impairment mediated by Spns1 deficiency. Unexpectedly, we found that a concurrent disruption of the vacuolar-type H C -ATPase (v-ATPase) subunit gene, atp6v0ca (ATPase, H C transporting, lysosomal, V0 subunit ca) led to suppression of the senescence induced by the Spns1 defect, whereas the sole loss of Atp6v0ca led to senescent embryos similar to the single spns1 mutation. Moreover, we discovered that the combined stable defect seen in the presence of both the spns1 and atp6v0ca mutant genes still subsequently induced premature autophagosome-lysosome fusion marked by insufficient acidity, while extending developmental life span, compared with the solely mutated spns1 defect. Our data suggest that Spns1 and the v-ATPase orchestrate proper autolysosomal biogenesis with optimal acidification that is critically linked to developmental senescence and survival.

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Mutations in the Novel Membrane Protein Spinster Interfere with Programmed Cell Death and Cause Neural Degeneration inDrosophila melanogaster

Cited by 127 publications

References 47 publications

The Drosophila caspases Strica and Dronc function redundantly in programmed cell death during oogenesis

The Drosophila caspases Strica and Dronc function redundantly in programmed cell death during oogenesis

Genome-Wide Association and Fine Mapping of Genetic Loci Predisposing to Colon Carcinogenesis in Mice

Autolysosome biogenesis and developmental senescence are regulated by both Spns1 and v-ATPase

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