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 blocks Notch cleavage and the subsequent signaling by its intracellular domain NICD.
“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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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 · see citing works
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 · see citing works
“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 · see citing works
“…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 · see citing works
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 252 · see citing works
“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 · see citing works
“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 · see citing works
“…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 · see citing works
“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 233 · see citing works
Liu, Y., Pathak, N. H., Kramer-Zucker, A. G., & Drummond, I. A. S. (2007) · Development · doi:10.1242/dev.02806 · Cited by 229 · see citing works
“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 · see citing works
“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 · see citing works
“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 · see citing works
“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 · see citing works
“, 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 · see citing works
“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 · see citing works
Self-citationMelchor, J. P., Pawlak, R., & Strickland, S. (2003) · The Journal of Neuroscience · doi:10.1523/jneurosci.23-26-08867.2003 · Cited by 202 · see citing works
“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 · see citing works
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 · see citing works
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 189 · see citing works
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 183 · see citing works
“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 · see citing works
“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 176 · see citing works
“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 · see citing works
“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 · see citing works
“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 · see citing works
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 172 · see citing works
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 · see citing works
“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 · see citing works
“-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 · see citing works
“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 · see citing works
“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 · see citing works
“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 · see citing works
“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 · see citing works
“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 153 · see citing works
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 152 · see citing works
Secretase inhibitors and modulators for Alzheimer’s disease treatment
Tomita, T. (2009) · Expert Review of Neurotherapeutics · doi:10.1586/ern.09.24 · Cited by 146 · see citing works
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 · see citing works
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 144 · see citing works
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 143 · see citing works
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 · see citing works
“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 · see citing works
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 141 · see citing works
“…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 141 · see citing works
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 · see citing works
“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 138 · see citing works
“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 136 · see citing works
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 132 · see citing works
“…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 134 · see citing works
Animal models of Alzheimer disease: historical pitfalls and a path forward
Cavanaugh, S. E. (2014) · ALTEX · doi:10.14573/altex.1310071 · Cited by 132 · see citing works
“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 · see citing works
“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 · see citing works
Daudet, N., Ariza‐McNaughton, L., & Lewis, J. H. (2007) · Development · doi:10.1242/dev.001842 · Cited by 127 · see citing works
“-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 127 · see citing works
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 · see citing works
“…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 127 · see citing works
“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 · see citing works
“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 · see citing works
“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 · see citing works
“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 · see citing works
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 117 · see citing works
“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 · see citing works
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 · see citing works
Cho, H. J., Kim, S., Jin, S. M., Hwang, E., Kim, Y. S., Huh, K., & Mook‐Jung, I. (2006) · Glia · doi:10.1002/glia.20451 · Cited by 115 · see citing works
“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.-H., Jones, J. M., Warchol, M. E., & Ornitz, D. (2012) · PLoS Biology · doi:10.1371/journal.pbio.1001231 · Cited by 122 · see citing works
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 110 · see citing works
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 · see citing works
“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 · see citing works
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 105 · see citing works
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 103 · see citing works
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 · see citing works
Crawford, T. Q., & Roelink, H. (2007) · Developmental Dynamics · doi:10.1002/dvdy.21083 · Cited by 102 · see citing works
“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 · see citing works
“…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
- 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
- Health Sciences › Medicine › Physiology › 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
About these checks
Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.
Statistics and arithmetic are recomputed, not judged.
Confidence bands are shown only for fields calibrated on our annotated test set. None is calibrated yet, so no band is shown.
What counts as a claim ›How we measure confidence ›How we check this ›
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