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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
Stages of embryonic development of the zebrafish
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The 'Arctic' APP mutation (E693G) causes Alzheimer's disease by enhanced Aβ protofibril formation
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Cited by
Sorted by citations
Items 101–200 of 498
The Notch signaling pathway in the cnidarian Hydra
Käsbauer, T., Towb, P., Alexandrova, O., David, C. N., Dall'Armi, E., Staudigl, A., Stiening, B., & Böttger, A. (2006) · Developmental Biology · doi:10.1016/j.ydbio.2006.11.022 · Cited by 99
Notch Signaling Inhibits Axon Regeneration
Bejjani, R. E., & Hammarlund, M. (2012) · Neuron · doi:10.1016/j.neuron.2011.11.017 · Cited by 96
“To test whether gamma-secretase inhibition can increase regeneration, we employed the small molecule N-[N-(3,5-difluorophenacetyl)-L-alanyl]-S-phenylglycine t-butyl ester (DAPT), which is a potent inhibitor of gamma-secretase activity and Notch signaling (Geling et al., 2002).”
MethodFunctional roles of Notch signaling in the cnidarian Nematostella vectensis
Marlow, H. Q., Röttinger, É., Boekhout, M., & Martindale, M. Q. (2011) · Developmental Biology · doi:10.1016/j.ydbio.2011.11.012 · Cited by 101
“, 2001) which prevents proteolytic cleavage of the Notch receptor thereby blocking the internalization and subsequent activity of the NICD as a transcriptional activator (Geling et al., 2002).”
BackgroundMethodTsao, P., Chen, F. F., Izvolsky, K. I., Walker, J. L., Kukuruzinska, M. A., Lü, J., & Cardoso, W. V. (2008) · Journal of Biological Chemistry · doi:10.1074/jbc.m801565200 · Cited by 101
Beyond γ-secretase activity: The multifunctional nature of presenilins in cell signalling pathways
Duggan, S. P., & McCarthy, J. V. (2015) · Cellular Signalling · doi:10.1016/j.cellsig.2015.10.006 · Cited by 107
“Indeed, Psen1 knockout animals display a predominant Notch loss-of function phenotype resulting from loss of γ-secretase cleavage of Notch, highlighting the importance of γsecretase in Notch signalling [23-25].”
Background5‐lipoxygenase as an endogenous modulator of amyloid beta formation in vivo
Chu, J., & Praticò, D. (2010) · Annals of Neurology · doi:10.1002/ana.22234 · Cited by 100
“5-LO Effect on the c-Secretase Does Not Influence Notch Processing Since the data so far support an effect of 5-LO on the csecretase complex, which is also involved in the processing of the Notch receptor, next we wanted to see whether this enzymatic pathway influenced the release of NICD.(16) Cells were transiently t…”
BackgroundMethodInfluentialZecchin, E., Filippi, A., Biemar, F., Tiso, N., Pauls, S., Ellertsdóttir, E., Gnügge, L., Bortolussi, M., Driever, W., & Argenton, F. (2006) · Developmental Biology · doi:10.1016/j.ydbio.2006.09.041 · Cited by 102
“Notch signaling was inactivated in vivo by N-[N-(3,5difluorophenacetyl)-L-alanyl]-S-phenylglycine t-butyl ester (DAPT, Calbiochem) treatment (Geling et al., 2002).”
BackgroundMethodReiterative use of the notch signal during zebrafish intrahepatic biliary development
Lorent, K., Moore, J. C., Siekmann, A. F., Lawson, N. D., & Pack, M. A. (2010) · Developmental Dynamics · doi:10.1002/dvdy.22220 · Cited by 99
“staged administration and withdrawal of the gamma-secretase inhibitor DAPT, an established pharmacological inhibitor of Notch signaling (Geling et al., 2002).”
BackgroundMethodInfluentialKim, H., Shin, J., Kim, S., Poling, J., Park, H., & Appel, B. (2008) · Developmental Dynamics · doi:10.1002/dvdy.21620 · Cited by 99
“DAPT (N-[N-(3,5-Difluorophenacetyl-L-alanyl]-S-phenylglycine-t-butyl ester; Calbiochem, La Jolla, CA) treatments were performed as previously described (Geling et al., 2002).”
BackgroundMethodPear, W. S., & Aster, J. C. (2004) · Current Opinion in Hematology · doi:10.1097/01.moh.0000143965.90813.70 · Cited by 99
Hudson, C., & Yasuo, H. (2006) · Development · doi:10.1242/dev.02466 · Cited by 98
“Application of DAPT has previously been shown to inhibit Notch-Delta signalling in zebrafish embryos (Geling et al., 2002).”
BackgroundIntra-Endodermal Interactions Are Required for Pancreatic β Cell Induction
Chung, W., & Stainier, D. Y. R. (2008) · Developmental Cell · doi:10.1016/j.devcel.2008.02.012 · Cited by 98
“Moreover, when we treated smo mutants at different developmental stages with DAPT, a gamma-secretase inhibitor that blocks the Notch signaling pathway (Geling et al., 2002), Tg(ins:GFP) expression was not rescued (data not shown).”
BackgroundWasson, C. W., Abignano, G., Hermes, H. M., Malaab, M., Ross, R. L., Jiménez, S. A., Chang, H. Y., Feghali‐Bostwick, C. A., & Galdo, F. D. (2020) · Annals of the Rheumatic Diseases · doi:10.1136/annrheumdis-2019-216542 · Cited by 98
Hudson, C., Lotito, S., & Yasuo, H. (2007) · Development · doi:10.1242/dev.002352 · Cited by 97
“Inhibitor treatments and establishing the approximate timing of penetration SB431542 (Tocris), U0126 (Calbiochem) and DAPT (Calbiochem) treatments in Ciona have been described previously (Hudson et al., 2003; Hudson and Yasuo, 2005; Hudson and Yasuo, 2006).”
InfluentialGu, B., Watanabe, K., Sun, P., Fallahi, M., & Dai, X. (2013) · Cell stem cell · doi:10.1016/j.stem.2013.04.012 · Cited by 93
“…in Pygo2-deficient MaSC/basal cells, we first treated these cells in 3D Matrigel culture with N-[(3,5-difluorophenyl)acetyl]-L-alanyl-2-phenylglycine-1,1-dimethylethyl ester (DAPT), a g-secretase inhibitor that blocks the activating, proteolytic cleavage of Notch receptors (Geling et al., 2002).”
Defining Single Molecular Forces Required for Notch Activation Using Nano Yoyo
Chowdhury, F., Li, I. T. S., Ngo, T. T. M., Leslie, B. J., Kim, B. C., Sokoloski, J. E., Weiland, E. A., Wang, X., Chemla, Y. R., Lohman, T. M., et al. (2016) · Nano Letters · doi:10.1021/acs.nanolett.6b01403 · Cited by 93
Kawamura, A., Koshida, S., Hijikata, H., Ohbayashi, A., Kondoh, H., & Takada, S. (2005) · Developmental Cell · doi:10.1016/j.devcel.2005.09.021 · Cited by 92
Ohata, S., Aoki, R., Kinoshita, S., Yamaguchi, M., Tsuruoka-Kinoshita, S., Tanaka, H., Wada, H., Watabe, S., Tsuboi, T., Masai, I., et al. (2011) · Neuron · doi:10.1016/j.neuron.2010.12.026 · Cited by 95
“Notch Maintains Neuroepithelial Polarity under Positive Regulation by Moe To examine whether the reduction in Notch activity seen in the moe mutant has anything to do with disturbance of neuroepithelial polarity and intercellular junctions, we treated the WT embryos with N-[N-(3,5-difluorophenacetyl)-L-alanyl]-S-pheny…”
Dontje, W., Schotte, R., Cupedo, T., Nagasawa, M., Scheeren, F. A., Gimeno, R., Spits, H., & Blom, B. (2005) · Blood · doi:10.1182/blood-2005-05-2090 · Cited by 92
Directional Notch trafficking in Sara endosomes during asymmetric cell division in the spinal cord
Kressmann, S., Campos, C., Castanon, I., Fürthauer, M., & González‐Gaitán, M. (2015) · Nature Cell Biology · doi:10.1038/ncb3119 · Cited by 91
Notch Activity Is Downregulated Just prior to Retinal Ganglion Cell Differentiation
Nelson, B. R., Gümüşçü, B., Hartman, B. H., & Reh, T. A. (2006) · Developmental Neuroscience · doi:10.1159/000090759 · Cited by 90
“Hence, inhibiting gamma-secretase during early development generates a phenotype indistinguishable from Notch loss of function phenotypes [ Geling et al., 2002 ].”
BackgroundMethodInfluentialKitzmann, M., Bonnieu, A., Duret, C., Vernus, B., Barro, M. V., Laoudj‐Chenivesse, D., Verdi, J. M., & Carnac, G. (2006) · Journal of Cellular Physiology · doi:10.1002/jcp.20688 · Cited by 89
“E-mail: gilles.carnac@crbm.cnrs.fr Received 26 October 2005; Accepted 14 April 2006 DOI: 10.1002/jcp.20688 Numb, which interacts with the intracellular portion of Notch and inhibits its activity (Guo et al., 1996).”
BackgroundInfluentialNOTCH inhibits osteoblast formation in inflammatory arthritis via noncanonical NF-κB
Zhang, H., Hilton, M. J., Anolik, J. H., Welle, S. L., Zhao, C., Yao, Z., Li, X., Wang, Z., Boyce, B. F., & Xing, L. (2014) · Journal of Clinical Investigation · doi:10.1172/jci68901 · Cited by 89
“Since persistent NOTCH inhibition (30) or activation (31) have detrimental effects on the skeleton, and high doses of NOTCH inhibitors have severe side effects in vivo, we decided to use low daily doses of DAPT.”
Krawitz, P. M., Haffner, C., Fluhrer, R., Steiner, H., Schmid, B., & Haass, C. (2005) · Journal of Biological Chemistry · doi:10.1074/jbc.m501645200 · Cited by 92
Self-citationShin, J., Poling, J., Park, H., & Appel, B. (2007) · Development · doi:10.1242/dev.001602 · Cited by 87
Ogando, J., Tardáguila, M., Díaz-Alderete, A., Usategui, A., Miranda-Ramos, V., Martínez-Herrera, D. J., de la Fuente, L., García-León, M. J., Moreno, M. C., Escudero, S. S., et al. (2016) · Scientific Reports · doi:10.1038/srep20223 · Cited by 90
Reelin and Notch1 Cooperate in the Development of the Dentate Gyrus
Sibbe, M., Forster, E., Başak, O., Taylor, V., & Frotscher, M. (2009) · Journal of Neuroscience · doi:10.1523/jneurosci.0958-09.2009 · Cited by 86
“To inhibit the -secretase-dependent S3 cleavage of Notch1, the -secretase inhibitor N-[N-(3,5-difluorophenacetyl)-lalanyl]-S-phenylglycine t-butyl ester (DAPT; Sigma-Aldrich) was used (Geling et al., 2002).”
BackgroundMethodInfluentialConservation of the Notch1 signaling pathway in gastrointestinal carcinoid cells
Kunnimalaiyaan, M., Traeger, K. A., & Chen, H. (2005) · American Journal of Physiology-Gastrointestinal and Liver Physiology · doi:10.1152/ajpgi.00146.2005 · Cited by 85
Landman, N., & Kim, T. (2004) · Cytokine & Growth Factor Reviews · doi:10.1016/j.cytogfr.2004.04.001 · Cited by 85
“[84] Geling A, Steiner H, Willem M, Bally-Cuif L, Haass C.”
BackgroundMethodAccelerated Amyloid Beta Pathogenesis by Bacterial Amyloid FapC
Javed, I., Zhang, Z., Adamčík, J., Andrikopoulos, N., Li, Y., Otzen, D. E., Lin, S., Mezzenga, R., Davis, T. P., Ding, F., et al. (2020) · Advanced Science · doi:10.1002/advs.202001299 · Cited by 83
Fluhrer, R., Multhaup, G., Schlicksupp, A., Okochi, M., Takeda, M., Lammich, S., Willem, M., Westmeyer, G., Bode, W., Walter, J., et al. (2003) · Journal of Biological Chemistry · doi:10.1074/jbc.m211485200 · Cited by 64
Self-citationNotch signalling mediates reproductive constraint in the adult worker honeybee
Duncan, E. J., Hyink, O., & Dearden, P. K. (2016) · Nature Communications · doi:10.1038/ncomms12427 · Cited by 80
Zebrafish as a tool in Alzheimer's disease research
Newman, M., Verdile, G., Martins, R. N., & Lardelli, M. T. (2010) · Biochimica et Biophysica Acta (BBA) - Molecular Basis of Disease · doi:10.1016/j.bbadis.2010.09.012 · Cited by 84
“The drug N-[N(3,5-difluorophenacetyl)-l-alanyl]-S-phenylglycine t-butyl ester (DAPT, [78]) is now commonly used to inhibit γ-secretase activity in zebrafish [79].”
BackgroundChu, J., & Praticò, D. (2011) · American Journal Of Pathology · doi:10.1016/j.ajpath.2010.12.032 · Cited by 81
RetractedMatsuda, M., & Chitnis, A. B. (2010) · Development · doi:10.1242/dev.052761 · Cited by 81
Identification of Modulators of Hair Cell Regeneration in the Zebrafish Lateral Line
Namdaran, P., Reinhart, K. E., Owens, K. N., Raible, D. W., & Rubel, E. W. (2012) · Journal of Neuroscience · doi:10.1523/jneurosci.3905-11.2012 · Cited by 82
“DAPT has been previously shown to diminish Notch signaling by preventing cleavage and release of the Notch intracellular domain (Geling et al., 2002), which results in an increase in the number of zebrafish lateral line hair cells regenerated after neomycin exposure (Ma et al., 2008).”
BackgroundVegfaa instructs cardiac muscle hyperplasia in adult zebrafish
Karra, R., Foglia, M. J., Choi, W.-Y., Belliveau, C., DeBenedittis, P., & Poss, K. D. (2018) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.1722594115 · Cited by 80
“However, vefgaa overexpression did not increase CM numbers in the presence of DAPT, even lowering counts by ∼30% (213 ± 51.6 CMs vs. 306.9 ± 79.3 CMs, P = 0.01, Student’s t test; Fig.”
MethodInfluentialEarly regionalization of the otic placode and its regulation by the Notch signaling pathway
Abelló, G., Khatri, S. B., Giráldez, F., & Alsina, B. (2007) · Mechanisms of Development · doi:10.1016/j.mod.2007.04.002 · Cited by 81
Bae, Y., Shimizu, T., & Hibi, M. (2005) · Development · doi:10.1242/dev.01710 · Cited by 79
“We also used a chemical compound, DAPT, which is a γ-secretase inhibitor that inhibits Notch signaling by preventing the generation of NotchICD (Geling et al., 2002), and RNAs for an activated form of Notch5 (zN5ICD) (Bae et al., 2003) or D ev el op m en t 1378 an antimorphic form of Xenopus Delta (xDlstu), which inhi…”
MethodInfluentialGuarnieri, A. L., Towers, C. G., Drasin, D. J., Oliphant, M. U. J., Andrysík, Z., Hotz, T. J., Vartuli, R. L., Linklater, E. S., Pandey, A., Khanal, S., et al. (2018) · Oncogene · doi:10.1038/s41388-018-0239-7 · Cited by 78
Mu, X., Isaac, C. E., Greco, N., Huard, J., & Weiss, K. R. (2013) · Frontiers in Oncology · doi:10.3389/fonc.2013.00143 · Cited by 77
Mandinova, A., Lefort, K., di Vignano, A. T., Stonely, W., Ostano, P., Chiorino, G., Iwaki, H., Nakanishi, J., & Dotto, G. P. (2008) · The EMBO Journal · doi:10.1038/emboj.2008.45 · Cited by 76
Lu, T.-M., Luo, Y., & Yu, J. (2012) · Development · doi:10.1242/dev.073833 · Cited by 75
Allosteric Modulation of PS1/γ-Secretase Conformation Correlates with Amyloid β42/40 Ratio
Uemura, K., Lill, C. M., Li, X., Peters, J. A., Ivanov, A., Fan, Z., Strooper, B. D., Bacskai, B. J., Hyman, B. T., & Berezovska, O. (2009) · PLoS ONE · doi:10.1371/journal.pone.0007893 · Cited by 75
Hiratochi, M., Nagase, H., Kuramochi, Y., Koh, C., Ohkawara, T., & Nakayama, K. (2007) · Nucleic Acids Research · doi:10.1093/nar/gkl1128 · Cited by 75
“N- [N-(3,5- DifluorophenacetylL- alanyl)]-S- phenylglycine t-Butyl Ester (DAPT) was purchased from Calbiochem (Germany) as a g-secretase inhibitor (18,19).”
Is it possible to improve neurodevelopmental abnormalities in Down syndrome?
Bartesaghi, R., Guidi, S., & Ciani, E. (2011) · Reviews in the Neurosciences · doi:10.1515/rns.2011.037 · Cited by 77
Xu, J., Liu, X., Chen, J., Zacharek, A., Cui, X., Savant‐Bhonsale, S., Liu, Z., & Chopp, M. (2008) · American Journal of Physiology-Cell Physiology · doi:10.1152/ajpcell.00310.2008 · Cited by 74
Identification of Pbx1 , a Potential Oncogene, as a Notch3 Target Gene in Ovarian Cancer
Park, J. T., Shih, I., & Wang, T. (2008) · Cancer Research · doi:10.1158/0008-5472.can-08-0517 · Cited by 74
“GSIhas been shown to potently inhibit g-secretase, thereby inactivating Notch signaling ( 18 , 19).”
BackgroundCurrent perspectives in zebrafish reverse genetics: Moving forward
Skromne, I., & Prince, V. (2008) · Developmental Dynamics · doi:10.1002/dvdy.21484 · Cited by 74
“, 1998), the gamma-secretase inhibitor DAPT (which blocks the Notch pathway; Geling et al., 2002), and SU5614 and SU1498 (which inhibit VEGF/Flk-1 tyrosine kinase signaling; Liang et al.”
BackgroundSeritrakul, P., & Gross, J. M. (2017) · PLoS Genetics · doi:10.1371/journal.pgen.1006987 · Cited by 74
Geling, A., Plessy, C., Rastegar, S., Strähle, U., & Bally‐Cuif, L. (2004) · Development · doi:10.1242/dev.01093 · Cited by 71
“This inhibitor (DAPT) prevents activity of the enzymatic complex cleaving Notch (De Strooper et al., 2001; Steiner and Haass, 2000) and induces faithful phenocopies of Notch signalling mutants when applied from blastula stages onwards (Geling et al., 2002).”
BackgroundMethodSelf-citationFaster embryonic segmentation through elevated Delta-Notch signalling
Liao, B., Jörg, D. J., & Oates, A. C. (2016) · Nature Communications · doi:10.1038/ncomms11861 · Cited by 70
Nicalin and its binding partner Nomo are novel Nodal signaling antagonists
Haffner, C., Frauli, M., Topp, S. D., Irmler, M., Hofmann, K., Regula, J. T., Bally‐Cuif, L., & Haass, C. (2004) · The EMBO Journal · doi:10.1038/sj.emboj.7600307 · Cited by 70
“fish system, which has been successfully used to recapitulate the defects in somite formation associated with the inhibition of Notch signaling ( Geling et al, 2002 ).”
BackgroundMethodSelf-citationWhat are you synching about? Emerging complexity of Notch signaling in the segmentation clock
Venzin, O. F., & Oates, A. C. (2019) · Developmental Biology · doi:10.1016/j.ydbio.2019.06.024 · Cited by 68
Winkler, E., Hobson, S., Fukumori, A., Dümpelfeld, B., Luebbers, T., Baumann, K., Haass, C., Hopf, C., & Steiner, H. (2009) · Biochemistry · doi:10.1021/bi801204g · Cited by 66
Self-citationvan Bebber, F., Hruscha, A., Willem, M., Schmid, B., & Haass, C. (2013) · Journal of Neurochemistry · doi:10.1111/jnc.12198 · Cited by 68
“This finding underlines the impact of Nrg1 type III as being a zBace1 substrate, which mediates physiological relevant processes comparable to the c-secretase substrate Notch (Geling et al. 2002).”
BackgroundSelf-citationNotch Ligands Expressed by Follicular Dendritic Cells Protect Germinal Center B Cells from Apoptosis
Yoon, S.-O., Zhang, X., Berner, P., Blom, B., & Choi, Y. S. (2009) · The Journal of Immunology · doi:10.4049/jimmunol.0803183 · Cited by 71
“ing pathway by blocking ligand-induced cleavage of Notch (33).”
BackgroundJiménez-Amilburu, V., Rasouli, S. J., Staudt, D., Nakajima, H., Chiba, A., Mochizuki, N., & Stainier, D. Y. R. (2016) · Cell Reports · doi:10.1016/j.celrep.2016.11.023 · Cited by 67
Selective Secretase Targeting for Alzheimer’s Disease Therapy
Miranda, A., Montiel, E., Ulrich, H., & Paz, C. (2021) · Journal of Alzheimer s Disease · doi:10.3233/jad-201027 · Cited by 66
Newman, M., Wilson, L., Verdile, G., Lim, A., Khan, I., Nik, S. H. M., Pursglove, S. E., Chapman, G., Martins, R. N., & Lardelli, M. T. (2013) · Human Molecular Genetics · doi:10.1093/hmg/ddt448 · Cited by 65
“We (32, 44) and others (45–48) have previously observed changes in Notch signalling in zebrafish embryos by examining changes in the expression of the neurogenin1 gene that is a under transcriptional regulation by Notch (45).”
BackgroundProgress toward Alzheimer's disease treatment: Leveraging the Achilles' heel of Aβ oligomers?
Fantini, J., Chahinian, H., & Yahi, N. (2020) · Protein Science · doi:10.1002/pro.3906 · Cited by 63
“Severe side effects triggered by γ-secretase inhibitors include related proteolytic processes such as those involved in Notch signaling.(24) After secretases, amyloid plaques had retained much attention for developing AD therapies.”
BackgroundNotch signaling pathway and Cdx2 expression in the development of Barrett's esophagus
Tamagawa, Y., Ishimura, N., Uno, G., Yuki, T., Kazumori, H., Ishihara, S., Amano, Y., & Kinoshita, Y. (2012) · Laboratory Investigation · doi:10.1038/labinvest.2012.56 · Cited by 64
An, Y., Xue, G., Shaobo, Y., Deng, M., Zhou, X., Yu, W., Ishibashi, T., Zhang, L., & Yan, Y. (2017) · Development · doi:10.1242/dev.150763 · Cited by 64
“In Drosophila embryos, it has been shown that overexpression of the Notch intracellular domain (NICD) leads to premature cell division in the ventral neuroectoderm (Hartenstein et al., 1994).”
MethodInfluentialFujimaki, R., Toyama, Y., Hozumi, N., & Tezuka, K. (2006) · Journal of Bone and Mineral Metabolism · doi:10.1007/s00774-005-0671-y · Cited by 64
“DAPT is a γ-secretase inhibitor, which blocks cleavage of the intracellular domain of all Notch proteins, and has been widely used in other systems [25–27].”
MethodThe metalloproteinase inhibitor Reck is essential for zebrafish DRG development
Prendergast, A. E., Linbo, T. H., Swarts, T., Ungos, J. M., McGraw, H. F., Krispin, S., Weinstein, B. M., & Raible, D. W. (2012) · Development · doi:10.1242/dev.072439 · Cited by 63
“We are unable to rescue DRG formation by treating sdp embryos with the Notch inhibitor DAPT (Geling et al., 2002) although we see an increase in DRG neurons when treating wild-type animals (data not shown), consistent with the notch1a mutant phenotype.”
MethodID4 controls mammary stem cells and marks breast cancers with a stem cell-like phenotype
Junankar, S. R., Baker, L. A., Roden, D. L., Nair, R., Elsworth, B., Gallego‐Ortega, D., Lacaze, P. A., Cazet, A., Nikolić, I., Teo, W. S., et al. (2015) · Nature Communications · doi:10.1038/ncomms7548 · Cited by 62
Notch Signaling Regulates Motor Neuron Differentiation of Human Embryonic Stem Cells
Ben-Shushan, E., Feldman, E., & Reubinoff, B. E. (2015) · Stem Cells · doi:10.1002/stem.1873 · Cited by 49
Distinct Biological Roles for the Notch Ligands Jagged-1 and Jagged-2
Choi, K. C., Ahn, Y., Gibbons, D. L., Tran, H. T., Creighton, C. J., Girard, L., Minna, J. D., Qin, F. X.-F., & Kurie, J. M. (2009) · Journal of Biological Chemistry · doi:10.1074/jbc.m109.003111 · Cited by 62
Cao, Q., Li, P., Lü, J., Dheen, S. T., Kaur, C., & Ling, E. A. (2010) · Journal of Neuroscience Research · doi:10.1002/jnr.22429 · Cited by 61
“, 2001) to prevent activation of the Notch response (Sastre et al., 2001; Geling et al., 2002).”
BackgroundGenomic editing opens new avenues for zebrafish as a model for neurodegeneration
Schmid, B., & Haass, C. (2013) · Journal of Neurochemistry · doi:10.1111/jnc.12460 · Cited by 69
Self-citationNotch Signaling in Postnatal Pituitary Expansion: Proliferation, Progenitors, and Cell Specification
Nantie, L. B., Himes, A. D., Getz, D. R., & Raetzman, L. T. (2014) · Molecular Endocrinology · doi:10.1210/me.2013-1425 · Cited by 61
Guiu, J., Bergen, D. J. M., de Pater, E., Islam, A. B. M. M. K., Ayllón, V., Gama-Norton, L., Ruiz‐Herguido, C., González, J., López-Bigas, N., Menéndez, P. R., et al. (2014) · The Journal of Experimental Medicine · doi:10.1084/jem.20131857 · Cited by 60
Protease inhibitors as potential disease-modifying therapeutics for Alzheimer’s disease
Beher, D., & Graham, S. L. (2005) · Expert Opinion on Investigational Drugs · doi:10.1517/13543784.14.11.1385 · Cited by 61
“Although those developmental phenotypes resulting from inactivation of Notch signalling are drastic and can be mimicked by γ-secretase inhibitor treatment in zebrafish [150] or Drosophila [151], they are less of a concern for the safety of a potential AD drug, which is mainly aimed at an elderly population.”
BackgroundGuha, S., Cullen, J. P., Morrow, D. J., Colombo, A. E., Lally, C., Walls, D., Redmond, E. M., & Cahill, P. A. (2011) · Basic Research in Cardiology · doi:10.1007/s00395-011-0189-5 · Cited by 59
Development and Notch Signaling Requirements of the Zebrafish Choroid Plexus
Bill, B., Balciunas, D., McCarra, J. A., Young, E. D., Xiong, T., Spahn, A. M., García‐Lecea, M., Korzh, V. P., Ekker, S. C., & Schimmenti, L. A. (2008) · PLoS ONE · doi:10.1371/journal.pone.0003114 · Cited by 61
Interaction with Notch determines endocytosis of specific Delta ligands in zebrafish neural tissue
Matsuda, M., & Chitnis, A. B. (2008) · Development · doi:10.1242/dev.027938 · Cited by 59
“DeltaD distribution in DAPT and DN-Su(H) embryos To further evaluate how increased deltaD production following loss of Notch signaling contributes to surface expression of DeltaD, we examined the changes in DeltaD distribution following other manipulations that inhibit Notch signaling: DAPT treatment, which inhibits t…”
BackgroundHer9 represses neurogenic fate downstream of Tbx1 and retinoic acid signaling in the inner ear
Radosevic, M., Robert‐Moreno, A., Coolen, M., Bally‐Cuif, L., & Alsina, B. (2011) · Development · doi:10.1242/dev.056093 · Cited by 59
“To assess whether her9 is regulated by this pathway, we blocked Notch activity using the -secretase inhibitor DAPT D E V E LO P M E N T (Geling et al., 2002).”
MethodSelf-citationLunatic fringe promotes the lateral inhibition of neurogenesis
Nikolaou, N., Watanabe‐Asaka, T., Gerety, S. S., Distel, M., Köster, R. W., & Wilkinson, D. G. (2009) · Development · doi:10.1242/dev.034736 · Cited by 57
“DAPT treatment was performed as described (Geling et al., 2002).”
BackgroundMethodInfluentialSmall molecules intercept Notch signaling and the early secretory pathway
Krämer, A., Mentrup, T., Kleizen, B., Rivera‐Milla, E., Reichenbach, D., Enzensperger, C., Nohl, R., Täuscher, E., Görls, H., Ploubidou, A., et al. (2013) · Nature Chemical Biology · doi:10.1038/nchembio.1356 · Cited by 57
Alzheimer's disease in a dish: promises and challenges of human stem cell models
Young, J. E., & Goldstein, L. S. B. (2012) · Human Molecular Genetics · doi:10.1093/hmg/dds319 · Cited by 57
Porazzi, P., Marelli, F., Benato, F., de Filippis, T., Calebiro, D., Argenton, F., Tiso, N., & Persani, L. (2012) · Endocrinology · doi:10.1210/en.2011-1888 · Cited by 58
Fbxw7 regulates Notch to control specification of neural precursors for oligodendrocyte fate
Snyder, J. L., Kearns, C. A., & Appel, B. (2012) · Neural Development · doi:10.1186/1749-8104-7-15 · Cited by 57
“To test this we used the γ-secretase inhibitor N-[N-(3,5difluoro- phenacetyl-l-alanyl)]-S-phenylglycine t-butyl ester (DAPT), which prevents release of the signaling-active Notch intracellular domain and produces phenotypes in zebrafish embryos that are indistinguishable from Notch pathway mutations [38].”
MethodWolbachia Control Stem Cell Behavior and Stimulate Germline Proliferation in Filarial Nematodes
Foray, V., Pérez‐Jiménez, M. M., Fattouh, N., & Landmann, F. (2018) · Developmental Cell · doi:10.1016/j.devcel.2018.03.017 · Cited by 57
The Notch ligand delta-1 is a hematopoietic development cofactor for plasmacytoid dendritic cells
Olivier, A., Lauret, E., Gonin, P., & Galy, A. H. M. (2005) · Blood · doi:10.1182/blood-2005-03-0970 · Cited by 57
Baba, K., Okada, K., Kinoshita, T., & Imaoka, S. (2009) · Toxicological Sciences · doi:10.1093/toxsci/kfp025 · Cited by 56
“To further evaluate the possibility that BPA effects are due to a disruption of Notch signaling, DAPT, an inhibitor of c-secretase activity (Geling et al., 2002), was added to the media in a final concentration of 20lM at st.”
InfluentialPostembryonic neuronal addition in Zebrafish dorsal root ganglia is regulated by Notch signaling
McGraw, H. F., Snelson, C. D., Prendergast, A. E., Suli, A., & Raible, D. W. (2012) · Neural Development · doi:10.1186/1749-8104-7-23 · Cited by 51
“t-butyl ester (DAPT; [24]; Sigma-Aldrich) was used to conditionally inhibit Notch signaling.”
BackgroundMethodNishad, R., Mukhi, D., Tahaseen, S. V., Mungamuri, S. K., & Pasupulati, A. K. (2019) · Journal of Biological Chemistry · doi:10.1074/jbc.ra119.008966 · Cited by 56
Dong, Z., Huo, J., Liang, A., Chen, J., Chen, G., & Liu, D. (2021) · The Science of The Total Environment · doi:10.1016/j.scitotenv.2021.146735 · Cited by 55
Nornes, S. (2003) · Experimental Cell Research · doi:10.1016/s0014-4827(03)00257-x · Cited by 55
CRAS-MÉNEUR, C. M. H., Li, L., Kopan, R., & Permutt, M. A. (2009) · Genes & Development · doi:10.1101/gad.1800209 · Cited by 56
“The endocrine area (in square microns) was determined by intensity thresholding using the morphometry measurement tools of ImageJ version 1.39p (National Institutes of Health, freely available at http://rsb.info.nih gov/ij/index.html; Girish and Vijayalakshmi 2004).”
MethodSobieszczuk, D. F., Poliakov, A. A., Xu, Q., & Wilkinson, D. G. (2010) · Genes & Development · doi:10.1101/gad.554510 · Cited by 54
γ-Secretase and its modulators: Twenty years and beyond
Xia, W. (2019) · Neuroscience Letters · doi:10.1016/j.neulet.2019.02.011 · Cited by 54
Zhang, C., Li, Q., Lim, C.-H., Qiu, X., & Jiang, Y. (2007) · Developmental Biology · doi:10.1016/j.ydbio.2007.01.034 · Cited by 53
Wnt-PLC-IP3-Connexin-Ca2+ axis maintains ependymal motile cilia in zebrafish spinal cord
Zhang, J., Chandrasekaran, G., Li, W., Kim, D., Jeong, I. Y., Lee, S.-H., Liang, T., Bae, J. Y., Choi, I., Kang, H., et al. (2020) · Nature Communications · doi:10.1038/s41467-020-15248-2 · Cited by 47
Progenitor Cell Dynamics in the Newt Telencephalon during Homeostasis and Neuronal Regeneration
Kirkham, M., Hameed, L. S., Berg, D. A., Wang, H., & Simon, A. (2014) · Stem Cell Reports · doi:10.1016/j.stemcr.2014.01.018 · Cited by 49
Jenkins, D. W., Ross, S. J., Veldman-Jones, M. H., Foltz, I. N., Clavette, B. C., Manchulenko, K., Eberlein, C., Kendrew, J., Petteruti, P., Cho, S., et al. (2012) · Molecular Cancer Therapeutics · doi:10.1158/1535-7163.mct-11-1027 · Cited by 52
“lead antibody MEDI0639 was selected by assessing the ability to modulate the interaction between Dll4 and the Notch1 receptor by FACS, Notch1-Dll4–dependent HUVEC proliferation (19, 24), and endothelial tube formation in a two-dimensional (2D) HUVEC fibroblast cell coculture assay (22, 25), inwhich inhibitionofNotch1-…”
BackgroundNornes, S., Newman, M., Verdile, G., Wells, S., Stoick-Cooper, C. L., Tucker, B., Frederich-Sleptsova, I., Martins, R. N., & Lardelli, M. T. (2007) · Human Molecular Genetics · doi:10.1093/hmg/ddm317 · Cited by 51
“To determine whether the apparent increase in psen1 transcription after loss of Psen1 protein might be due to a feedback mechanism dependent upon g-secretase activity, we used QRT – PCR to determine the levels of psen1 mRNA in embryos at 48 h post-fertilisation (hpf) that had been treated for 42 h with the g-secretase…”
MethodBruton, F. A., Kaveh, A., Stewart, K. R., Matrone, G., Oremek, M. E. M., Solomonidis, E. G., Tucker, C. S., Mullins, J. J., Lucas, C. D., Brittan, M., et al. (2022) · Developmental Cell · doi:10.1016/j.devcel.2022.05.014 · Cited by 53
Notch signaling regulates midline cell specification and proliferation in zebrafish
Latimer, A. J., & Appel, B. (2006) · Developmental Biology · doi:10.1016/j.ydbio.2006.05.039 · Cited by 50
Mahler, J., Filippi, A., & Driever, W. (2010) · Journal of Neuroscience · doi:10.1523/jneurosci.4769-10.2010 · Cited by 50
“The -secretase inhibitor N-[N-(3,5-difluorophenacetyl)-L-alanyl]-S-phenylglycine-t-butyl ester (DAPT) was dissolved at 10 mM in DMSO and diluted to a final concentration of 100 M in embryo medium (Geling et al., 2002).”
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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