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A γ‐secretase inhibitor blocks Notch signaling in vivo and causes a severe neurogenic phenotype in zebrafish
Open accessAbstract
Inhibition of amyloid beta-peptide (Abeta) production by blocking gamma-secretase activity is at present one of the most promising therapeutic strategies to slow progression of Alzheimer's disease pathology. gamma-secretase inhibitors apparently block Abeta generation via interference with presenilin (PS) function. Besides being an essential component of the gamma-secretase complex, PS itself may be an aspartyl protease with gamma-secretase activity, which is not only required for Abeta production but also for a similar proteolytic process involved in Notch signaling. Here we demonstrate that treatment of zebrafish embryos with a known gamma-secretase inhibitor affects embryonic development in a manner indistinguishable from Notch signaling deficiencies at morphological, molecular and biochemical levels. This indicates severe side-effects of gamma-secretase inhibitors in any Notch-dependent cell fate decision and demonstrates that the zebrafish is an ideal vertebrate system to validate compounds that selectively affect Abeta production, but not Notch signaling, under in vivo conditions.
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“DAPT, which prevents Notch cleavage and subsequent signaling by its intracellular domain, NICD”
From HB-EGF is Necessary and Sufficient for Müller Glia Dedifferentiation and Retina Regeneration (2012) · cites this paper as Geling et al., 2002
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Cites
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Cited by
Sorted by citations
Soluble protein oligomers in neurodegeneration: lessons from the Alzheimer's amyloid β-peptide
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“After overnight culture, DAPT was added at concentrations that have been proven to inhibit -secretase activity and interfere with Notch signaling in zebrafish (Geling et al. 2002) and in chick cultured embryos (Dale et al. 2003).”
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Hamley, I. W. (2012) · Chemical Reviews · doi:10.1021/cr3000994 · Cited by 892
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100 Years and Counting: Prospects for Defeating Alzheimer's Disease
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Take five—BACE and the γ‐secretase quartet conduct Alzheimer's amyloid β‐peptide generation
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“Accordingly, deleterious side effects have been observed in vivo (Geling et al, 2002).”
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Canonical notch signaling functions as a commitment switch in the epidermal lineagePreprint
Blanpain, C., Lowry, W. E., Pasolli, H. A., & Fuchs, E. V. (2006) · Genes & Development · doi:10.1101/gad.1477606 · Cited by 444
“Where indicated, cells were also treated with DAPT (N-[N-{3,5-difluorophenacetyl}-lalanyl]-S-phenylglycine t-butyl ester) to inhibit Notch processing and NICD production ( Geling et al. 2002 ).”
BackgroundMethodInfluentialMath1 regulates development of the sensory epithelium in the mammalian cochlea
Woods, C., Montcouquiol, M., & Kelley, M. W. (2004) · Nature Neuroscience · doi:10.1038/nn1349 · Cited by 413
Mesp1 Acts as a Master Regulator of Multipotent Cardiovascular Progenitor Specification
Bondue, A., Lapouge, G., Paulissen, C., Semeraro, C., Iacovino, M., Kyba, M., & Blanpain, C. (2008) · Cell stem cell · doi:10.1016/j.stem.2008.06.009 · Cited by 403
“To investigate whether Notch signaling was necessary for the cardiovascular specification induced by Mesp1, we treated ESCs with N-[N-(3,5-Difluorophenacetyl)-L-alanyl]-S-phenylglycine t-butyl ester (DAPT), a gamma-secretase inhibitor that prevents Notch activation ( Geling et al., 2002 ) while at the same time induci…”
MethodGenetic and cellular analyses of zebrafish atrioventricular cushion and valve development
Beis, D., Bartman, T., Jin, S., Scott, I. C., D’Amico, L., Ober, E. A., Verkade, H. M., Frantsve‐Hawley, J., Field, H. A., Wehman, A. M., et al. (2005) · Development · doi:10.1242/dev.01970 · Cited by 360
“-Secretase is required for the activation of the Notch signaling pathway (reviewed by Mumm and Kopan, 2000) and DAPT-treated zebrafish embryos have somitogenesis and neurogenesis phenotypes identical to those caused by a loss of Notch signaling (Geling et al., 2002).”
BackgroundSelf-citationNotch-responsive cells initiate the secondary transition in larval zebrafish pancreas
Parsons, M. J., Pisharath, H., Yusuff, S., Moore, J. C., Siekmann, A., Lawson, N., & Leach, S. (2009) · Mechanisms of Development · doi:10.1016/j.mod.2009.07.002 · Cited by 354
“(2) Antagonizing Notch-signaling with a commonly used antagonist, DAPT (Geling et al., 2002), drastically reduces expression from either transgene (Fig.”
BackgroundMethodInfluentialvon Rotz, R. C., Kohli, B. M., Bosset, J., Meier, M. G., Suzuki, T., Nitsch, R. M., & Konietzko, U. (2004) · Journal of Cell Science · doi:10.1242/jcs.01323 · Cited by 366
“Inhibition of γ-secretase by L-685,458 (Shearman et al., 2000) or DAPT (Geling et al., 2002; Sastre et al., 2001) completely abolished the formation of nuclear AICD spots from APP-citrine fusion proteins.”
BackgroundInfluentialNew Insights Into the Pathogenesis of Alzheimer's Disease
Fan, L., Mao, C., Hu, X., Zhang, S., Yang, Z., Hu, Z., Sun, H., Fan, Y., Dong, Y., Yang, J., et al. (2020) · Frontiers in Neurology · doi:10.3389/fneur.2019.01312 · Cited by 362
Hedgehog Signaling Is Required for Adult Blood Stem Cell Formation in Zebrafish Embryos
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Human distal airways contain a multipotent secretory cell that can regenerate alveoli
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Control of the Reversibility of Cellular Quiescence by the Transcriptional Repressor HES1
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Notch1 is required for maintenance of the reservoir of adult hippocampal stem cells
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“Activation of Notch1 requires gammasecretase cleavage, therefore GSI also inhibit Notch1 activity (Geling et al., 2002) and SGZ progenitor proliferation (Breunig et al., 2007).”
BackgroundZebrafish assays for drug toxicity screening
Rubinstein, A. L. (2006) · Expert Opinion on Drug Metabolism & Toxicology · doi:10.1517/17425255.2.2.231 · Cited by 296
“For example, the γ-secretase inhibitor N-[N-(3,5-difluorophenacetyl)-L-alanyl]-S-phenylglycine t-butyl ester causes defects in somitogenesis that are also found in zebrafish Notch pathway mutants [55].”
BackgroundLammich, S., Okochi, M., Takeda, M., Kaether, C., Capell, A., Zimmer, A., Edbauer, D., Walter, J., Steiner, H., & Haass, C. (2002) · Journal of Biological Chemistry · doi:10.1074/jbc.m206872200 · Cited by 288
Self-citationZebrafish embryos as models for embryotoxic and teratological effects of chemicals
Yang, L., Ho, N. Y., Alshut, R., Legradi, J., Weiß, C., Reischl, M., Mikut, R., Liebel, U., Müller, F., & Strähle, U. (2009) · Reproductive Toxicology · doi:10.1016/j.reprotox.2009.04.013 · Cited by 293
Applications of CRISPR–Cas systems in neuroscience
Heidenreich, M., & Zhang, F. (2015) · Nature reviews. Neuroscience · doi:10.1038/nrn.2015.2 · Cited by 290
A zebrafish model of tauopathy allows in vivo imaging of neuronal cell death and drug evaluation
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Self-citationHB-EGF is Necessary and Sufficient for Müller Glia Dedifferentiation and Retina Regeneration
Wan, J., Ramachandran, R., & Goldman, D. (2012) · Developmental Cell · doi:10.1016/j.devcel.2011.11.020 · Cited by 262
“…in the injured retina To investigate if Notch signaling is necessary for injury-dependent MG dedifferentiation and proliferation we took advantage of the γ-secretase inhibitor DAPT, which prevents Notch cleavage and subsequent signaling by its intracellular domain, NICD (Geling et al., 2002).”
BackgroundKawakami, Y., Raya, Á., Raya, R. M., Rodrı́guez-Esteban, C., & Belmonte, J. C. I. (2005) · Nature · doi:10.1038/nature03512 · Cited by 271
Synchrony Dynamics During Initiation, Failure, and Rescue of the Segmentation Clock
Riedel-Kruse, I. H., Müller, C., & Oates, A. C. (2007) · Science · doi:10.1126/science.1142538 · Cited by 263
Inhibition of oncogenic Wnt signaling through direct targeting of β-catenin
Grossmann, T. N., Yeh, J. T.-H., Bowman, B. R., Chu, Q., Moellering, R. E., & Verdine, G. L. (2012) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.1208396109 · Cited by 268
Chapouton, P., Skupien, P., Hesl, B., Coolen, M., Moore, J. C., Madelaine, R., Kremmer, E., Faus-Kessler, T., Blader, P., Lawson, N. D., et al. (2010) · Journal of Neuroscience · doi:10.1523/jneurosci.6170-09.2010 · Cited by 259
“To test this hypothesis, we first blocked Notch activity pharmacologically in vivo by applying to the swimming water the small-molecule DAPT, an inhibitor of the -secretase complex preventing the generation of NICD, hence Notch signaling (Geling et al., 2002).”
MethodSelf-citationMoriyama, M., Osawa, M., Mak, S., Ohtsuka, T., Yamamoto, N., Han, H., Delmas, V., Kageyama, R., Beermann, F., Larue, L., et al. (2006) · The Journal of Cell Biology · doi:10.1083/jcb.200509084 · Cited by 254
“…immunostaining of embryonic skin using an antibody against As an alternative avenue for analyzing the function of Notch signaling in Mbs, we adopted an embryonic skin organ culture system by blocking Notch activation with a pharmacological inhibitor for γ-secretase (Geling et al., 2002).”
Vegfc/Flt4 signalling is suppressed by Dll4 in developing zebrafish intersegmental arteries
Hogan, B. M., Herpers, R., Witte, M., Heloterä, H., Alitalo, K. K., Duckers, H. J., & Schulte‐Merker, S. (2009) · Development · doi:10.1242/dev.039990 · Cited by 254
Torchia, J., Golbourn, B. J., Feng, S., Ho, K. C., Sin‐Chan, P., Vasiljevic, A., Norman, J. D., Guilhamon, P., Garzia, L., Agamez, N. M. R., et al. (2016) · Cancer Cell · doi:10.1016/j.ccell.2016.11.003 · Cited by 259
“To evaluate functional significance of NOTCH and BMP signaling,weusedDAPT (N-[N-(3,5-difluorophenacetyl)-L-alanyl]S-phenylglycine t-butyl ester), a g-secretase inhibitor (Geling et al., 2002), and dorsomorphin (DM) (Yu et al.”
BackgroundMethodLi, Y., Paczesny, S., Lauret, E., Poirault‐Chassac, S., Bordigoni, P., Mekhloufi, F., Héquet, O., Bertrand, Y., Ouyang, J., Stoltz, J., et al. (2008) · The Journal of Immunology · doi:10.4049/jimmunol.180.3.1598 · Cited by 250
“DAPT (N-[N-(3,5-difluorophenacetyl)-L-alanyl]-S-phenylglycine t-butyl ester; Sigma-Aldrich) is an inhibitor of the -secretase responsible for the cleavage of Notch induced by ligand binding and a well-known inhibitor of the Notch signaling pathway (28).”
BackgroundNotch Signaling Regulates the Extent of Hair Cell Regeneration in the Zebrafish Lateral Line
Ma, E. Y., Rubel, E. W., & Raible, D. W. (2008) · Journal of Neuroscience · doi:10.1523/jneurosci.4372-07.2008 · Cited by 244
“…with the -secretase inhibitor DAPT results in the overproduction of HCs. DAPT treatment phenocopies mind bomb mutants, which inactivate an E3 ubiquitin ligase necessary for efficient Notch signaling (Itoh et al., 2003) and is reversed by expression of processed Notch (Geling et al., 2002).”
BackgroundMethodResultInfluentialNotch activity acts as a sensor for extracellular calcium during vertebrate left–right determination
Raya, Á., Kawakami, Y., Rodrı́guez-Esteban, C., Ibañes, M., Rasskin‐Gutman, D., Rodríguez‐León, J., Büscher, D., Feijó, J. A., & Belmonte, J. C. I. (2004) · Nature · doi:10.1038/nature02190 · Cited by 235
“To test the first assumption experimentally, we downregulated Notch signalling either by using DAPT ( N -[ N -(3,5-difluorophenacetyl- l -alanyl)]- S -phenylglycine t -butyl ester), a γ-secretase inhibitor known to block the Notch pathway in vivo”
MethodBorghese, L., Bohačiaková, D., Opitz, T., Haupt, S., Leinhaas, A., Steinfarz, B., Koch, P., Edenhofer, F., Hampl, A., & Brüstle, O. (2010) · Stem Cells · doi:10.1002/stem.408 · Cited by 239
Liu, Y., Pathak, N. H., Kramer-Zucker, A. G., & Drummond, I. A. S. (2007) · Development · doi:10.1242/dev.02806 · Cited by 238
“Zebrafish embryos treated with DAPT were kept at 28°C until analysis at 34 hpf. Control embryos were mock treated with embryo medium containing the same concentration of DMSO carrier only.”
InfluentialNeuronal regeneration in a zebrafish model of adult brain injury
Kishimoto, N., Shimizu, K., & Sawamoto, K. (2011) · Disease Models & Mechanisms · doi:10.1242/dmm.007336 · Cited by 220
“To study the role of Notch 1 signaling in the injuryinduced responses in our zebrafish model, we blocked Notch 1 signaling in vivo by adding DAPT, a -secretase inhibitor that impairs the generation of NICD, to the aquarium water (Geling et al., 2002).”
MethodDynamic Fgf signaling couples morphogenesis and migration in the zebrafish lateral line primordium
Lecaudey, V., Cakan‐Akdogan, G., Norton, W., & Gilmour, D. T. (2008) · Development · doi:10.1242/dev.025981 · Cited by 220
“We next blocked Notch activity completely by treating embryos with the γ-secretase inhibitor DAPT, a widely used antagonist of Notch signaling (Geling et al., 2002).”
MethodKelly, M. C., Chang, Q., Pan, A., Lin, X., & Chen, P. (2012) · Journal of Neuroscience · doi:10.1523/jneurosci.5420-11.2012 · Cited by 218
“6C,D), cultures treated with DAPT, which inhibits -secretase-dependent cleavage of Notch required for downstream signaling (Geling et al., 2002), had an ectopic sensory region made up almost entirely of MyoVI-positive hair cells with only a few nonsensory cells throughout (Fig.”
BackgroundCheng, H., Miner, J. H., Lin, M., Tansey, M. G., Roth, K. A., & Kopan, R. (2003) · Development · doi:10.1242/dev.00697 · Cited by 211
“, 2001) or whole animals (Geling et al., 2002; Micchelli et al., 2003) were extremely informative and demonstrated specificity for Notch signaling by inhibition of γ-secretase with no general toxicity.”
BackgroundWall, D. S., Mears, A. J., McNeill, B., Mazerolle, C. J., Thurig, S., Wang, Y., Kageyama, R., & Wallace, V. A. (2009) · The Journal of Cell Biology · doi:10.1083/jcb.200805155 · Cited by 208
“To address whether Shh induction of Hes1 and Hes5 requires Notch signaling, we used a widely used chemical inhibitor of the ␥ -secretase complex, N -[ N -(3,5-difl uorophenacetyl )-l -alanyl]-S-phenylglycine t-butyl ester (DAPT), to inhibit propagation of the Notch pathway ( Geling et al., 2002 ).”
Intramembrane Proteolysis by γ-Secretase
Steiner, H., Fluhrer, R., & Haass, C. (2008) · Journal of Biological Chemistry · doi:10.1074/jbc.r800010200 · Cited by 207
Self-citationMelchor, J. P., Pawlak, R., & Strickland, S. (2003) · The Journal of Neuroscience · doi:10.1523/jneurosci.23-26-08867.2003 · Cited by 202
“Presenilin-null neurons are deficient in A production (Zhang et al., 2000), and presenilin inhibitors are effective in preventing A formation in cell culture (Beher et al., 2001); however, the clinical use of these inhibitors might lead to side effects such as decreased Notch processing ( Geling et al., 2002; Roncarat…”
BackgroundGleevec inhibits β-amyloid production but not Notch cleavage
Netzer, W. J., Dou, F., Cai, D., Veach, D. R., Jean, S., Li, Y., Bornmann, W. G., Clarkson, B., Xu, H., & Greengard, P. (2003) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.1534745100 · Cited by 192
Kaether, C., Lammich, S., Edbauer, D., Ertl, M., Rietdorf, J., Capell, A., Steiner, H., & Haass, C. (2002) · The Journal of Cell Biology · doi:10.1083/jcb.200201123 · Cited by 187
Self-citationInhibition of amyloid beta toxicity in zebrafish with a chaperone-gold nanoparticle dual strategy
Javed, I., Peng, G., Xing, Y., Yu, T., Zhao, M., Käkinen, A., Faridi, A., Parish, C. L., Ding, F., Davis, T. P., et al. (2019) · Nature Communications · doi:10.1038/s41467-019-11762-0 · Cited by 190
Interaction of MSC with tumor cells
Melzer, C., Yang, Y., & Hass, R. (2016) · Cell Communication and Signaling · doi:10.1186/s12964-016-0143-0 · Cited by 189
“growth of breast cancer cells in co-culture experiments [36, 56].”
BackgroundWang, Y., Kim, R., Gunasekara, D. B., Reed, M. I., DiSalvo, M., Nguyen, D. L., Bultman, S. J., Sims, C. E., Magness, S. T., & Allbritton, N. L. (2017) · Cellular and Molecular Gastroenterology and Hepatology · doi:10.1016/j.jcmgh.2017.10.007 · Cited by 184
“and is thought to act as a Notch activator.(43,44) In contrast, DAPT, a Notch inhibitor, increased Muc2 expression, suggesting that Notch inhibition increased Goblet cell production under these conditions.”
BackgroundResultIngram, W. J., McCue, K., Tran, T.-T., Hallahan, A. R., & Wainwright, B. J. (2007) · Oncogene · doi:10.1038/sj.onc.1210767 · Cited by 178
“To address this, an inhibitor of Notch pathway signalling, N-[N-(3,5-Difluorophenacetyl-L-alanyl)]-S-phenylglycine t-butyl ester (DAPT; Geling et al., 2002), was used to treat cells during stimulation with Shh.”
MethodHainaud, P., Contrerès, J.-O., Villemain, A., Liu, L.-X., Plouët, J., Tobelem, G., & Dupuy, É. (2006) · Cancer Research · doi:10.1158/0008-5472.can-05-4226 · Cited by 175
“Presenilin inhibitors are known to inhibit the Notch pathway (38, 39 ).”
BackgroundTransient inactivation of Notch signaling synchronizes differentiation of neural progenitor cells
Nelson, B. R., Hartman, B. H., Georgi, S. A., Lan, M. S., & Reh, T. A. (2007) · Developmental Biology · doi:10.1016/j.ydbio.2007.01.001 · Cited by 174
“One γ-secretase inhibitor, DAPT, has been shown to phenocopy various Notch mutations in both zebrafish and Drosophila (Geling et al., 2002; Micchelli et al., 2003) and downregulates Hes1 and Hes5 gene expression and reporter activity (Ong et al., 2006; Nelson et al., 2006).”
InfluentialÖzbudak, E. M., & Lewis, J. H. (2008) · PLoS Genetics · doi:10.1371/journal.pgen.0040015 · Cited by 167
γ-secretases: from cell biology to therapeutic strategies
Bergmans, B. A., & Strooper, B. D. (2010) · The Lancet Neurology · doi:10.1016/s1474-4422(09)70332-1 · Cited by 179
Intercellular Coupling Regulates the Period of the Segmentation Clock
Herrgen, L., Ares, S., Morelli, L. G., Schröter, C. J., Jülicher, F., & Oates, A. C. (2010) · Current Biology · doi:10.1016/j.cub.2010.06.034 · Cited by 163
“We recently introduced a general framework building on previous efforts [13, 17, 21, 22] that combines the spatial and temporal aspects of the segmentation clock and adds delayed coupling between neighboring oscillators [20] (Fig.”
InfluentialBarten, D. M., Guss, V. L., Corsa, J. A., Loo, A., Hansel, S. B., Zheng, M., Munoz, B., Srinivasan, K., Wang, B., Robertson, B. J., et al. (2005) · The Journal of Pharmacology and Experimental Therapeutics · doi:10.1124/jpet.104.075408 · Cited by 159
“-Secretase inhibitors have also been shown to induce notched wings in Drosophila (Micchelli et al., 2003) and to alter embryonic development in zebrafish (Geling et al., 2002).”
BackgroundA Notch feeling of somite segmentation and beyond
Rida, P. C. G., Minh, N. L., & Jiang, Y. (2003) · Developmental Biology · doi:10.1016/j.ydbio.2003.07.003 · Cited by 158
“Importantly, the expression of cycling genes like deltaC and her1 are disrupted in Notch pathway mutants (Gajewski et al., 2003; Geling et al., 2002; Henry et al., 2002; Holley et al., 2000, 2002; Jiang et al., 2000; Oates and Ho, 2002; Sieger et al., 2003).”
BackgroundMartone, R., Zhou, H., Atchison, K., Comery, T., Xu, J. Z., Huang, X.-Y., Gong, X., Jin, M., Kreft, A., Harrison, B., et al. (2009) · Journal of Pharmacology and Experimental Therapeutics · doi:10.1124/jpet.109.152975 · Cited by 163
“Although the consequences of inhibiting GS processing of many of these substrates are currently unknown, the inhibition of Notch processing is known to have specific adverse events (Geling et al., 2002; van den Brandt et al., 2004).”
BackgroundNotch signaling regulates regeneration in the avian retina
Hayes, S., Nelson, B. R., Buckingham, B., & Reh, T. A. (2007) · Developmental Biology · doi:10.1016/j.ydbio.2007.09.046 · Cited by 141
“Previous studies have shown that DAPTand inhibitory mutations in the Notch pathway have the same effect on development (Geling et al., 2002; Micchelli et al., 2003; Nelson et al., 2006; Nelson et al., 2007).”
BackgroundSadowski, M., Pankiewicz, J., Scholtzova, H., Ripellino, J. A., Li, Y., Schmidt, S. D., Mathews, P. M., Fryer, J. D., Holtzman, D. M., Sigurdsson, E. M., et al. (2004) · The American Journal of Pathology · doi:10.1016/s0002-9440(10)63355-x · Cited by 154
“Compared to vaccination(87) or -secretase inhibitors,(88) blocking of pathological chaperones is not associated with the risk of an autoimmune reaction or affecting multiple signaling pathways including Notch-1 and wnt.(86) Animals treated with A 12–28P did not produce a humoral response related to the peptide’s small…”
BackgroundPasini, A., Amiel, A., Rothbächer, U., Roure, A., Lemaire, P., & Darras, S. (2006) · PLoS Biology · doi:10.1371/journal.pbio.0040225 · Cited by 152
“To gain a better insight into the temporal requirement of the Delta/ Notch pathway and its mechanisms of action in the determination of CESN numbers, embryos at early neurula, late neurula, and early tailbud stage were treated with the csecretase inhibitor, DAPT [46], followed by ETR in situ hybridization and DAPI sta…”
InfluentialFLRT2 and FLRT3 act as repulsive guidance cues for Unc5‐positive neurons
Yamagishi, S., Hampel, F., Hata, K., del Toro, D., Schwark, M., Kvachnina, E., Bastmeyer, M., Yamashita, T., Tarabykin, V. S., Klein, R., et al. (2011) · The EMBO Journal · doi:10.1038/emboj.2011.189 · Cited by 162
Hébert, S. S., Serneels, L., Dejaegere, T., Horré, K., Dąbrowski, M., Baert, V., Annaert, W. G., Hartmann, D., & Strooper, B. D. (2004) · Neurobiology of Disease · doi:10.1016/j.nbd.2004.08.002 · Cited by 158
Secretase inhibitors and modulators for Alzheimer’s disease treatment
Tomita, T. (2009) · Expert Review of Neurotherapeutics · doi:10.1586/ern.09.24 · Cited by 148
Notch signaling is required for normal prostatic epithelial cell proliferation and differentiation
Wang, X.-D., Leow, C. C., Zha, J., Tang, Z., Modrusan, Z. D., Radtke, F., Aguet, M., de Sauvage, F. J., & Gao, W. (2005) · Developmental Biology · doi:10.1016/j.ydbio.2005.11.009 · Cited by 145
Scheppke, L., Murphy, E. A., Zarpellon, A., Hofmann, J. J., Merkulova, A. A., Shields, D. J., Weis, S. M., Byzova, T. V., Ruggeri, Z. M., Iruela‐Arispe, M. L., et al. (2011) · Blood · doi:10.1182/blood-2011-04-348706 · Cited by 153
Doi, H., Iso, T., Sato, H., Yamazaki, M., Matsui, H., Tanaka, T., Manabe, I., Arai, M., Nagai, R., & Kurabayashi, M. (2006) · Journal of Biological Chemistry · doi:10.1074/jbc.m602749200 · Cited by 144
Campbell, W. A., Yang, H., Zetterberg, H., Baulac, S., Sears, J. A., Liu, T., Wong, S. T. C., Zhong, T. P., & Xia, W. (2006) · Journal of Neurochemistry · doi:10.1111/j.1471-4159.2006.03648.x · Cited by 142
“TUNEL staining of embryos treated with 100 lM DAPT (n ¼ 12, 100%; Fig.”
BackgroundMethodResultInfluentialHsiao, C., You, M., Guh, Y.-J., Ma, M., Jiang, Y., & Hwang, P. (2007) · PLoS ONE · doi:10.1371/journal.pone.0000302 · Cited by 142
Involvement of Delta/Notch signaling in zebrafish adult pigment stripe patterning
Hamada, H., Watanabe, M., Lau, H. E., Nishida, T., Hasegawa, T., Parichy, D. M., & Kondo, S. (2013) · Development · doi:10.1242/dev.099804 · Cited by 143
“…Notch signaling To determine whether melanophore survival depends on the Delta/Notch signal, we incubated 1- to 1.5-month-old adult, wildtype fish with DAPT, which blocks cleavage of the Notch intracellular domain (NICD) fragment of the Notch receptor (Dovey et al., 2001; Geling et al., 2002).”
MethodInfluentialWang, Q., & Lu, Q. (2017) · Nature Communications · doi:10.1038/s41467-017-00767-2 · Cited by 149
Making the final cut: Pathogenic amyloid-β peptide generation by γ-secretase
Steiner, H., Fukumori, A., Tagami, S., & Okochi, M. (2018) · Cell Stress · doi:10.15698/cst2018.11.162 · Cited by 133
“Unfortunately, since such pan-GSIs inhibit both Aβ and Notch ICD (NICD) production, severe side effects were observed when administered in vivo, mainly due to disturbance of Notch signaling [143-146].”
BackgroundSelf-citationHeterogeneity and Fgf dependence of adult neural progenitors in the zebrafish telencephalon
Ganz, J., Kaslin, J., Hochmann, S., Freudenreich, D., & Brand, M. (2010) · Glia · doi:10.1002/glia.21012 · Cited by 137
“For the DAPT experiments, the g-secretase inhibitor DAPT (Calbiochem), which specifically prevents NICD formation and blocks Notch signal transduction (Dovey et al., 2001; Geling et al., 2002), was added to a final concentration of 5 lM to the medium, the control cells were incubated in DMSO.”
MethodAncestral Notch-mediated segmentation revealed in the cockroach Periplaneta americana
Pueyo, J. I., Lanfear, R., & Couso, J. P. (2008) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.0804093105 · Cited by 140
Notch Activity Modulates the Responsiveness of Neural Progenitors to Sonic Hedgehog Signaling
Kong, J. H., Yang, L., Dessaud, É., Chuang, K., Moore, D. M., Rohatgi, R., Briscoe, J., & Novitch, B. G. (2015) · Developmental Cell · doi:10.1016/j.devcel.2015.03.005 · Cited by 141
“…to moderate (1 nM) or high (4 nM) amounts of Shh and varying amounts of the γ -secretase inhibitor DAPT (N-[N-(3,5-Difluorophenacetyl)-L-alanyl]-S-phenylglycine t-butyl ester) to reduce Notch receptor cleavage and downstream signaling (Dovey et al., 2001; Geling et al., 2002; Dessaud et al., 2007).”
Mandel, K., Yang, Y., Schambach, A., Glage, S., Otte, A., & Hass, R. (2013) · Stem Cells and Development · doi:10.1089/scd.2013.0249 · Cited by 139
Animal models of Alzheimer disease: historical pitfalls and a path forward
Cavanaugh, S. E. (2014) · ALTEX · doi:10.14573/altex.1310071 · Cited by 132
“Drugs targeting γ-secretase tend to cross-react with the Notch-1 protein, which plays an essential role in cell-fate determination (Geling et al., 2002; Micchelli et al., 2003).”
Kubo, F., Takeichi, M., & Nakagawa, S. (2005) · Development · doi:10.1242/dev.01856 · Cited by 132
“To address this issue, we prepared retinal explants from earlier embryos (E5) and treated them for 24 hours with the γ-secretase inhibitor DAPT, which prevents the cleavage of the intracellular portion of Notch and thus functions as a Notch-signaling inhibitor (Dovey et al., 2001; Geling et al., 2002).”
MethodNeves, J., Parada, C., Chamizo, M., & Giráldez, F. (2011) · Development · doi:10.1242/dev.060657 · Cited by 129
Daudet, N., Ariza‐McNaughton, L., & Lewis, J. H. (2007) · Development · doi:10.1242/dev.001842 · Cited by 127
“-secretase activity can be inhibited with small cell-permeant molecules such as DAPT, leading to a blockade of Notch signalling (Dovey et al., 2001; Geling et al., 2002).”
BackgroundWeggen, S., Eriksen, J. L., Sagi, S. A., Pietrzik, C. U., Golde, T. E., & Koo, E. H. (2003) · Journal of Biological Chemistry · doi:10.1074/jbc.m304824200 · Cited by 126
Khalturin, K., Anton-Erxleben, F., Milde, S., Plötz, C., Wittlieb, J., Hemmrich, G., & Bosch, T. C. G. (2007) · Developmental Biology · doi:10.1016/j.ydbio.2007.06.013 · Cited by 125
“…cell differentiation and to investigate the function of the Notch pathway in vivo, we treated polyps for 48 to 96 h with DAPT which blocks Notch activity by inhibiting the γ-secretase-dependent cleavage that releases the Notch intracellular domain (Geling et al., 2002; James et al., 2004).”
InfluentialAlzheimer disease: Amyloidogenesis, the presenilins and animal models
Newman, M., Musgrave, I., & Lardelli, M. T. (2006) · Biochimica et Biophysica Acta (BBA) - Molecular Basis of Disease · doi:10.1016/j.bbadis.2006.12.001 · Cited by 129
“Treatment of embryos with DAPT affects somitogenesis and neurogenesis by 24 hpf [138].”
BackgroundBittner, T., Fuhrmann, M., Burgold, S., Jung, C. K. E., Volbracht, C., Steiner, H., Mitteregger, G., Kretzschmar, H. A., Haass, C., & Herms, J. (2009) · The Journal of Neuroscience · doi:10.1523/jneurosci.2288-09.2009 · Cited by 123
“GSIs block -secretase processing of APP as well as numerous other type I membrane proteins, including Notch (Geling et al., 2002; Kopan and Ilagan, 2004).”
BackgroundSelf-citationRole of Delta-like-4/Notch in the Formation and Wiring of the Lymphatic Network in Zebrafish
Geudens, I., Herpers, R., Hermans, K., Segura, I., de Almodóvar, C. R., Bussmann, J., Smet, F. D., Vandevelde, W., Hogan, B. M., Siekmann, A. F., et al. (2010) · Arteriosclerosis Thrombosis and Vascular Biology · doi:10.1161/atvbaha.110.203034 · Cited by 124
“exposing dechorionated 24-hpf embryos to N-[N-(3,5-difluorophenacetyl)-L-alanyl]-Sphenylglycine t-butyl ester (DAPT), a well known γ-secretase inhibitor (γ-secretase inhibitor IX; Calbiochem), that has been previously used to block Notch signaling in zebrafish embryos.(16)”
The genetics and embryology of zebrafish metamerism
Holley, S. A. (2007) · Developmental Dynamics · doi:10.1002/dvdy.21162 · Cited by 123
“Moreover, treatment of embryos with a chemical inhibitor of notch signaling, DAPT, does not affect the anterior somites (Geling et al., 2002; Mara et al., 2007).”
Backgroundsox9b Is a Key Regulator of Pancreaticobiliary Ductal System Development
Delous, M., Yin, C., Shin, D., Ninov, N., Carten, J. D., Pan, L., Ma, T. P., Farber, S. A., Moens, C. B., & Stainier, D. Y. R. (2012) · PLoS Genetics · doi:10.1371/journal.pgen.1002754 · Cited by 120
Zebrafish models for the functional genomics of neurogenetic disorders
Kabashi, E., Brustein, E., Champagne, N., & Drapeau, P. (2010) · Biochimica et Biophysica Acta (BBA) - Molecular Basis of Disease · doi:10.1016/j.bbadis.2010.09.011 · Cited by 126
“APPs possess a functional gamma-secretase complex to produce amyloid-beta [15] and inhibition of gamma-secretase [16] or knockdown of Pen-2 [17], anothermember of the presinilin complex, blocks Notch signaling to produce a severe neurogenic phenotype.”
BackgroundBernardos, R. L., Lentz, S. I., Wolfe, M. S., & Raymond, P. A. (2004) · Developmental Biology · doi:10.1016/j.ydbio.2004.11.018 · Cited by 117
4-Dimensional light-sheet microscopy to elucidate shear stress modulation of cardiac trabeculation
Lee, J., Fei, P., Packard, R. R. S., Kang, H., Xu, H., Baek, K. I., Jen, N., Chen, J., Yen, H., Kuo, C. ‐. J., et al. (2016) · Journal of Clinical Investigation · doi:10.1172/jci83496 · Cited by 116
Cho, H. J., Kim, S., Jin, S. M., Hwang, E., Kim, Y. S., Huh, K., & Mook‐Jung, I. (2007) · Glia · doi:10.1002/glia.20451 · Cited by 98
“For example, knock out of the presenilin 1 (PS1) gene, which is a core component of g-secretase complex, resulted in lethality in a mouse model at the embryonic stage (Geling et al., 2002; Shen et al., 1997).”
BackgroundHuh, S., Jones, J. M., Warchol, M. E., & Ornitz, D. M. (2012) · PLoS Biology · doi:10.1371/journal.pbio.1001231 · Cited by 111
Presenilin-1 uses phospholipase D1 as a negative regulator of β-amyloid formation
Cai, D., Netzer, W. J., Zhong, M., Lin, Y., Du, G., Frohman, M. A., Foster, D. A., Sisodia, S. S., Xu, H., Gorelick, F. S., et al. (2006) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.0510708103 · Cited by 115
Priming, initiation and synchronization of the segmentation clock by deltaD and deltaC
Mara, A., Schroeder, J., Chalouni, C. M., & Holley, S. A. (2007) · Nature Cell Biology · doi:10.1038/ncb1578 · Cited by 108
“and causes a segmentation defect when added to zebrafish embryo”
BackgroundEvolutionary conserved role of ptf1a in the specification of exocrine pancreatic fates.
Zecchin, E., Mavropoulos, A., Devos, N., Filippi, A., Tiso, N., Meyer, D., Peers, B., Bortolussi, M., & Argenton, F. (2004) · Developmental Biology · doi:10.1016/j.ydbio.2003.12.016 · Cited by 115
Inhibition of ??-Secretase as a Therapeutic Intervention for Alzheimer???s Disease
Evin, G. M., Sernee, M. F., & Masters, C. L. (2006) · CNS Drugs · doi:10.2165/00023210-200620050-00002 · Cited by 106
Genetics of Alzheimer's Disease. A Rapidly Evolving Field
Serretti, A., Olgiati, P., & Ronchi, D. D. (2007) · Journal of Alzheimer s Disease · doi:10.3233/jad-2007-12108 · Cited by 105
Fang, F., Yu, Q., Arancio, O., Chen, D., Gore, S. S., Yan, S. S., & Yan, S. F. (2018) · Human Molecular Genetics · doi:10.1093/hmg/ddy017 · Cited by 103
Crawford, T. Q., & Roelink, H. (2007) · Developmental Dynamics · doi:10.1002/dvdy.21083 · Cited by 102
“N-[N-(3,5-difluorophenacetyl)-l-alanyl]-S-phenylglycine t-butyl ester (DAPT) efficiently blocks the presenilin– -secretase complex (Dovey et al., 2001) and, as a consequence, efficiently prevents activation of the Notch response (Sastre et al., 2001; Geling et al., 2002).”
Generation of pulmonary neuroendocrine cells and SCLC-like tumors from human embryonic stem cells
Chen, H. J., Poran, A., Unni, A. M., Huang, S. X. L., Elemento, O., Snoeck, H., & VARMUS, H. E. (2019) · The Journal of Experimental Medicine · doi:10.1084/jem.20181155 · Cited by 102
“…on these reports, we exposed LPs between day 25 and 55 to N-[(3,5-difluorophenyl)acetyl]-L-alanyl-2-phenyl]glycine-1,1dimethylethyl ester (DAPT; Geling et al., 2002)—a known inhibitor of γ-secretase, the protease that normally cleaves NOTCH receptors to yield a transcriptionally active,…”
Method
Metadata
- Authors
- Geling, A., Steiner, H., Willem, M., Bally‐Cuif, L., & Haass, C.
- Affiliations
- Technical University of Munich (DE)
- Adolf-Butenandt-Institut für Physiologische Chemie, Physikalische Biochemie und Zellbiologie (DE)
- Venue
- The EMBO Reports
- Published
- 2002-07-01
- Volume
- 3
- Issue
- 7
- Pages
- 688-694
- ISSN
- 1469-221X (ISSN-L)
- 1469-3178
- OpenAlex
- W2082694975
- Cited by
- 497
- References
- 56
- Citations by year
- 2026: 7 · 2025: 13 · 2024: 12 · 2023: 7 · 2022: 13 · 2021: 15 · 2020: 14 · 2019: 27 · 2018: 13 · 2017: 17 · 2016: 25 · 2015: 16 · 2014: 19 · 2013: 28 · 2012: 34
- FWCI
- 11.57
- Type
- journal article
- Language
- en
- Open access
- green
- europepmc.org
- Locations
- EMBO Reports (publishedVersion)
- Europe PMC (PubMed Central) (publishedVersion)
- PubMed (publishedVersion)
- PubMed Central (publishedVersion)
- Funders
- Deutsche Forschungsgemeinschaft
- Topics
- Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Alzheimer's disease research and treatments
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Developmental Biology and Gene Regulation
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Cell Biology › Zebrafish Biomedical Research Applications
- Keywords
- gamma-secretase inhibitors, Notch signaling, presenilin, amyloid-beta, Alzheimer's disease, neurogenesis, zebrafish embryos, embryonic development, off-target effects, cell fate determination, adverse drug reactions
- MeSH terms
- Alzheimer Disease, Animals, Cell Line, Enzyme Inhibitors, gamma-Aminobutyric Acid, Humans, Membrane Proteins, Microinjections, Endopeptidases, Phenotype, RNA, Messenger, Triglycerides, Zebrafish, Signal Transduction, Aspartic Acid Endopeptidases, Amyloid beta-Protein Precursor, In Situ Hybridization, Body Patterning, Receptors, Notch, Presenilin-1, Amyloid Precursor Protein Secretases
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