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APLP1 promotes dFoxO-dependent cell death in Drosophila

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Abstract

The amyloid precursor like protein-1 (APLP1) belongs to the amyloid precursor protein family that also includes the amyloid precursor protein (APP) and the amyloid precursor like protein-2 (APLP2). Though the three proteins share similar structures and undergo the same cleavage processing by α-, β- and γ-secretases, APLP1 shows divergent subcellular localization from that of APP and APLP2, and thus, may perform distinct roles in vivo. While extensive studies have been focused on APP, which is implicated in the pathogenesis of Alzheimer’s disease, the functions of APLP1 remain largely elusive. Here we report that the expression of APLP1 in Drosophila induces cell death and produces developmental defects in wing and thorax. This function of APLP1 depends on the transcription factor dFoxO, as the depletion of dFoxO abrogates APLP1-induced cell death and adult defects. Consistently, APLP1 up-regulates the transcription of dFoxO target hid and reaper-two well known pro-apoptotic genes. Thus, the present study provides the first in vivo evidence that APLP1 is able to induce cell death, and that FoxO is a crucial downstream mediator of APLP1’s activity.

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Acknowledgments

We thank Dr. Merders, Dr. Partridge and the Bloomington Drosophila Stock Center for fly stocks. This work is supported by the National Basic Research Program of China (973 Program) (2010CB944901, 2011CB943903), National Natural Science Foundation of China (31071294, 31171413, 31371490), the Specialized Research Fund for the Doctoral Program of Higher Education of China (20120072110023), and Shanghai Committee of Science and Technology (09DZ2260100, 14JC1406000).

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Correspondence to Lei Xue.

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10495_2015_1097_MOESM1_ESM.docx

Fig. S1 APLP1 induces cell death and defects in wing development. Fluorescent images of GFP expression (a) or acridine orange staining (b, c) of wing discs from 3rd instar larvae and light images of adult wing (e-g) are shown. dpp-Gal4 was used as a control (b,f), or to drive the expression of GFP (a,e) or APLP1 (c, g). The lower panels are high magnification of the boxed areas in the upper panels. d shows the statistical analysis of acridine orange-positive cells in band c, whereas h shows the statistical analysis of the acv presence in f andg.***: P ≤ 0.001. Genotypes: UAS-GFP/+ ; dpp-Gal4/+ (a,e); dpp-Gal4/+ (b, f); dpp-Gal4/UAS-APLP1 (c,g) (DOCX 201 kb)

10495_2015_1097_MOESM2_ESM.docx

Fig. S2 APLP1 induces cell death in the wing pouch area. Fluorescent images of GFP expression (a) or acridine orange staining (b, c) of wing discs from 3rd instar larvae are shown. sd-Gal4 was used as a control (b), or to drive the expression of GFP (a) or APLP1 (c). The lower panels are high magnification of the boxed areas in the upper panels. Genotypes: sd-Gal4/+ ; UAS-GFP/+ (a); sd-Gal4/+ (b);sd-Gal4/+ ; UAS-APLP1/+ (c) (DOCX 159 kb)

10495_2015_1097_MOESM3_ESM.docx

Fig. S3 Loss of dfoxO suppresses APLP1-induced blistered wing phenotype. (a-c) Light images of adult wings are shown. Compared with the sd-Gal4 control (a), expression of APLP1 produced a blistered wing phenotype (b), which was suppressed in heterozygous dfoxO mutants (c). The red arrow indicates a blister on the wing. d is the statistical analysis of the presence of blistered wing.***, P ≤ 0.001. Genotypes: sd-Gal4/+ (a); sd-Gal4/+ ;UAS-APLP1/+ (b); sd-Gal4/+ ;UAS-APLP1/dfoxO △94 (c) (DOCX 155 kb)

10495_2015_1097_MOESM4_ESM.docx

Fig.S4 APLP1 induces dFoxO-mediated cell death in the notum. Fluorescent images of acridine orange staining of notum tips of the wing discs from 3rd instar larvae are shown(a-c). Compared with the pnr-Gal4 control (a), expression of APLP1 resulted in enhanced cell death in the notum (b), which was suppressed by the expression of a dfoxO RNAi (c). The lower panels are high magnification of the boxed areas in the upper panels. d is the statistical analysis of acridine orange-positive cells in a-c.***, P ≤ 0.001; **, P ≤ 0.01. Genotypes: pnr-Gal4/+ (a); pnr-Gal4/UAS-APLP1 (b); pnr-Gal4 UAS-APLP1/UAS-dfoxO-IR#1 (c) (DOCX 118 kb)

10495_2015_1097_MOESM5_ESM.docx

Fig. S5 APLP1 induces cell death in the nervous system. Fluorescent images of GFP expression (a, e) or acridine orange staining (b, c, f, g) of the ventral nervecord (VNC) or eye disc from 3rd instar larvae are shown. elav-Gal4 and GMR-Gal4 were used as controls(b, f), or to drive the expression of GFP (a, e) or APLP1 (c, g). d shows statistical analysis of AO positive cells in b and c.**, P < 0.01. h shows statistical analysis of AO positive cells in f and g.***: P ≤ 0.001. Genotypes: elav-Gal4/+ ; UAS-GFP/+ (a); elav-Gal4/+ (b);elav-Gal4/+ ; UAS-APLP1/+ (c); UAS-GFP/+ ; GMR-Gal4/+ (e); GMR-Gal4/+ (f); GMR-Gal4/UAS-APLP1 (g) (DOCX 177 kb)

10495_2015_1097_MOESM6_ESM.docx

Fig. S6 APLP2 induces cell death and defects in wing development. Acridine orange staining (a, b) of wing discs from 3rd instar larvae and light images of adult wing (d,e) are shown. ptc-Gal4 was used as a control (a,d), or to drive the expression of APLP2 (b, e). The lower panels are high magnification of the boxed areas in the upper panels. c shows the statistical analysis of acridine orange-positive cells in a and b. f shows the statistical analysis of theacv presence in dande.***: P ≤ 0.001. Genotypes: ptc-Gal4/+ (a, d); ptc-Gal4/UAS-APLP2(b,e) (DOCX 275 kb)

10495_2015_1097_MOESM7_ESM.docx

Fig. S7 APLP2 induces cell death and defects in the wing and thorax. Acridine orange staining (a, b) of wing discs from 3rd instar larvae and light images of adult wing (c, d) or thorax (e, f) are shown. sd-Gal4 (a, c) or pnr-Gal4 (e) was used as controls, or to drive the expression of APLP2(b, d, f). The lower panels are high magnification of the boxed areas in the upper panels. Genotypes: sd-Gal4/+ (a, c); sd-Gal4/+ ; UAS-APLP2/+ (b, d); pnr-Gal4/+ (e); UAS-APLP2/+ ; pnr-Gal4/+ (f) (DOCX 251 kb)

10495_2015_1097_MOESM8_ESM.docx

Fig. S8 APPL induces cell death in the nervous system. Fluorescent images of RFP expression (a) or acridine orange staining (b, c) of the ventral nervecord from 3rd instar larvae are shown. APPL-Gal4 was used as a control (b), or to drive the expression of RFP (a) or APPLsd (c). The dashed white box indicates the ventral nerve cord middle line. The lower panels are high magnification of the boxed areas in the upper panels. d shows the statistical analysis of AO positive cells in b and c.**, P < 0.01. Genotypes: APPL-Gal4/+ ; UAS-RFP/+ (a); APPL-Gal4/+ (b);APPL-Gal4/+ ; UAS-APPLsd/+ (c) (DOCX 191 kb)

10495_2015_1097_MOESM9_ESM.docx

Fig. S9 Expression of FoxO proteins produces the loss-of-acv phenotype. (a-c) Light images of adult wings are shown. Compared with the ptc-Gal4 control (a), expression of dFoxO or hFoxO3a resulted in the loss-of-acv phenotype (b, c). The lower panels are high magnification of the boxed areas in the upper panels. d shows the statistical analysis of the presence of acv in a-c.***, P ≤ 0.001. Genotypes: ptc-Gal4/+ (a); ptc-Gal4/+ ;UAS-dFoxO/+ (b); ptc-Gal4/+ ;UAS-hFoxO3a/+ (c) (DOCX 220 kb)

10495_2015_1097_MOESM10_ESM.docx

Fig. S10 Expression of APLP2 activates the transcription of FoxO target genes. Light images of Drosophila 3rd instar wing discs are shown. X-Gal staining of hid-LacZ and reaper-LacZ reporters in the wing pouch (a, c) are dramatically up-regulated by the expression of APLP2 (b, d) (DOCX 190 kb)

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Wang, X., Ma, Y., Zhao, Y. et al. APLP1 promotes dFoxO-dependent cell death in Drosophila . Apoptosis 20, 778–786 (2015). https://doi.org/10.1007/s10495-015-1097-1

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