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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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Items 201–300 of 498
Shankaran, S. S., Sieger, D., Schröter, C. J., Czepe, C., Pauly, M.-C., Laplante, M. A., Becker, T. S., Oates, A. C., & Gajewski, M. (2007) · Developmental Biology · doi:10.1016/j.ydbio.2007.01.004 · Cited by 50
“DAPT treatment was done as described to inhibit the cleavage of the intracellular domain of the Notch receptor by presinilin with a concentration of 100 μ M (Geling et al., 2002).”
Li, X., Cui, J., Yu, Y., Li, W., Hou, Y., Wang, X., Qin, D.-P., Zhao, C., Yao, X., Zhao, J., et al. (2016) · PLoS ONE · doi:10.1371/journal.pone.0151147 · Cited by 49
Notch Antagonists: Potential Modulators of Cancer and Inflammatory Diseases
Kumar, R., Juillerat‐Jeanneret, L., & Golshayan, D. (2016) · Journal of Medicinal Chemistry · doi:10.1021/acs.jmedchem.5b01516 · Cited by 50
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Notch signaling can regulate endoderm formation in zebrafish
Kikuchi, Y., Verkade, H. M., Reiter, J. F., Kim, C., Chitnis, A. B., Kuroiwa, A., & Stainier, D. Y. R. (2004) · Developmental Dynamics · doi:10.1002/dvdy.10483 · Cited by 49
“…(DN presenilin) (Leimer et al., 1999) or treating early embryos with the -secretase inhibitor DAPT (N-[N(3,5-difluorophenacetyl-L-alanyl)]-Sphenylglycine t-butyl ester; Dovey et al., 2001; Geling et al., 2002) did not appear to increase the number of endodermal cells either (data not shown).”
BackgroundMethodInfluentialRoach, G., Wallace, R. H., Cameron, A., Özel, R. E., Hongay, C. F., Baral, R., Andreescu, S., & Wallace, K. N. (2013) · Developmental Biology · doi:10.1016/j.ydbio.2013.01.013 · Cited by 49
“DAPT treatment Notch signaling was inhibited in vivo using N-[N-(3,5-difluorophenacetyl)-L-alanyl]-Sphenylglycine t-butyl ester (DAPT) (Geling et al., 2002).”
BackgroundMethodInfluentialYang, T., Arslanova, D., Gu, Y., Augelli‐Szafran, C. E., & Xia, W. (2008) · Molecular Brain · doi:10.1186/1756-6606-1-15 · Cited by 51
“DAPT was specifically tested in zebrafish [ 61 ].”
BackgroundMethodInfluentialNuclear Factor κB-Dependent Neurite Remodeling Is Mediated by Notch Pathway
Bonini, S. A., Ferrari‐Toninelli, G., Uberti, D. L., Montinaro, M., Buizza, L., Lanni, C., Grilli, M., & Memo, M. (2011) · Journal of Neuroscience · doi:10.1523/jneurosci.1113-11.2011 · Cited by 48
“DAPT is a well known Notch1 pharmacological inhibitor (Sastre et al., 2001; Geling et al., 2002; Crawford and Roelink, 2007), preventing Notch1 intracellular cleavage, which is required for NICD nuclear translocation and signaling activation.”
BackgroundRelease of a membrane-bound death domain by γ-secretase processing of the p75NTR homolog NRADD
Gowrishankar, K., Zeidler, M. G., & Vincenz, C. (2004) · Journal of Cell Science · doi:10.1242/jcs.01263 · Cited by 49
“In vertebrates, application of γ-secretase inhibitors is toxic to the development of embryos and, in view of the large number of γ-secretase substrates recently described, even adults might be affected (Geling et al., 2002).”
BackgroundMethodEnteric neural crest cells regulate vertebrate stomach patterning and differentiation
Faure, S., McKey, J., Sagnol, S., & Barbara, P. D. S. (2014) · Development · doi:10.1242/dev.118422 · Cited by 48
“DAPT is a small cell-permeant molecule that inhibits γ-secretase activity, leading to the blockage of Notch signaling (Geling et al., 2002) and the efficient inhibition of Hairy2 expression in the intestinal mesenchyme (supplementary material Fig.”
BackgroundTaylor, S. M., Álvarez-Delfín, K., Saade, C. J., Thomas, J. L., Thummel, R., Fadool, J. M., & Hitchcock, P. F. (2015) · Investigative Ophthalmology & Visual Science · doi:10.1167/iovs.15-17616 · Cited by 44
Perineurial Glia Require Notch Signaling during Motor Nerve Development but Not Regeneration
Binari, L. A., Lewis, G. M., & Kucenas, S. (2013) · Journal of Neuroscience · doi:10.1523/jneurosci.4893-12.2013 · Cited by 48
“Additionally, DAPT has been shown to phenocopy Notch signaling mutants in zebrafish (Geling et al., 2002).”
BackgroundKim, W.-K., Meliton, V., Tetradis, S., Weinmaster, G., Hahn, T. J., Carlson, M., Nelson, S. F., & Parhami, F. (2009) · Journal of Bone and Mineral Research · doi:10.1359/jbmr.091024 · Cited by 46
“DAPT blocks canonical Notch signaling by inhibiting g-secretase activity and the production of NICD when Notch ligands bind to Notch receptor.((45)) DAPT treatment significantly reduced both 20S and Shh induction of HES-1 mRNA expression, as well as baseline HES-1 mRNA expression compared with control cells (see Fig.”
BackgroundCOUP-TFI controls Notch regulation of hair cell and support cell differentiation
Tang, L. S., Alger, H. M., & Pereira, F. A. (2006) · Development · doi:10.1242/dev.02536 · Cited by 48
“…of several proteins (Kimberly and Wolfe, 2003), inhibition of - secretase produces phenotypes similar to those of Notch mutations in zebrafish (Geling et al., 2002) and Drosophila (Micchelli et al., 2003), strongly suggesting that the disruption of Notch signaling is the dominant effect of…”
BackgroundMethodHaraguchi, K., Suzuki, T., Koyama, N., Kumano, K., Nakahara, F., Matsumoto, A., Yokoyama, Y., Sakata‐Yanagimoto, M., Masuda, S., Takahashi, T., et al. (2009) · The Journal of Immunology · doi:10.4049/jimmunol.0803036 · Cited by 47
“To confirm that the NK cell differentiation was Notch dependent, we added a -secretase inhibitor, DAPT, which strongly inhibits ligand-dependent Notch activation (24, 25).”
BackgroundA new training procedure for studying discrimination learning in fish
Agrillo, C., Petrazzini, M. E. M., Piffer, L., Dadda, M., & Bisazza, A. (2012) · Behavioural Brain Research · doi:10.1016/j.bbr.2012.02.025 · Cited by 47
“ebrafish, guppies, goldfish, and stickleback, among others, have een successfully employed to study learning, memory, and visual erception, to screen new drugs, to identify the function of brain enes, and to model human psychopathology and neurodegeneraive diseases [1–6].”
Mirkovic, I., Pylawka, S., & Hudspeth, A. J. (2012) · Biology Open · doi:10.1242/bio.2012570 · Cited by 44
“We therefore examined the possible role of the Notch pathway in hair-cell rearrangements by exposing 2 dpf embryos to the c-secretase inhibitor DAPT, an inhibitor of Notch signaling (Geling et al., 2002).”
MethodAnd Lophotrochozoa makes three: Notch/Hes signaling in annelid segmentation
Rivera, A. S., & Weisblat, D. A. (2008) · Development Genes and Evolution · doi:10.1007/s00427-008-0264-6 · Cited by 47
“It has been shown to be a specific inhibitor of Notch signaling in protostomes, deuterostomes, and a cnidarian (Geling et al. 2002; Micchelli et al. 2002; Kasbauer et al. 2007).”
BackgroundResultSuccessive cleavage of β-amyloid precursor protein by γ-secretase
Funamoto, S., Tagami, S., Okochi, M., & Morishima‐Kawashima, M. (2020) · Seminars in Cell and Developmental Biology · doi:10.1016/j.semcdb.2020.04.002 · Cited by 44
Tandon, A., Singh, S. J., Gupta, M., Singh, N., Shankar, J., Arjaria, N., Goyal, S., & Chaturvedi, R. K. (2020) · Journal of Hazardous Materials · doi:10.1016/j.jhazmat.2020.122052 · Cited by 49
Relationship between Delta-like and proneural bHLH genes during chick retinal development
Nelson, B. R., & Reh, T. A. (2008) · Developmental Dynamics · doi:10.1002/dvdy.21550 · Cited by 45
Mechanisms of tentacle morphogenesis in the sea anemone Nematostella vectensis
Fritz, A. E., Ikmi, A., Seidel, C. W., Paulson, A., & Gibson, M. C. (2013) · Development · doi:10.1242/dev.088260 · Cited by 45
“DAPT inhibits γsecretase, the enzyme responsible for cleaving the Notch intracellular domain (NICD) (Geling et al., 2002).”
BackgroundLilly, B., & Kennard, S. (2008) · Physiological Genomics · doi:10.1152/physiolgenomics.90318.2008 · Cited by 47
Filippi, A., Tiso, N., Deflorian, G., Zecchin, E., Bortolussi, M., & Argenton, F. (2005) · Proceedings of the National Academy of Sciences of the United States of America · doi:10.1073/pnas.0407284102 · Cited by 46
Notch signalling stabilises boundary formation at the midbrain-hindbrain organiser
Tossell, K., Kiecker, C. M., Wizenmann, A., Lang, E., & Irving, C. (2011) · Development · doi:10.1242/dev.070318 · Cited by 44
“First, we used a chemical inhibitor of -secretase activity, DAPT (N-[N-(3,5-difluorophenacetyl)-l-alanyl]-Sphenylglycine t-butyl ester), which prevents cleavage of the intracellular Notch fragment, thus preventing activation of target genes (Geling et al., 2002).”
MethodEvidence for Notch signaling involvement in retinal regeneration of adult newt
Nakamura, K., & Chiba, C. (2006) · Brain Research · doi:10.1016/j.brainres.2006.12.032 · Cited by 44
The Impact of Intermittent Hypoxia on Metabolism and Cognition
Shobatake, R., Ota, H., Takahashi, N., Ueno, S., Sugie, K., & Takasawa, S. (2022) · International Journal of Molecular Sciences · doi:10.3390/ijms232112957 · Cited by 45
Presenilin mouse and zebrafish models for dementia: Focus on neurogenesis
van Tijn, P., Kamphuis, W., Marlatt, M. W., Hol, E. M., & Lucassen, P. J. (2010) · Progress in Neurobiology · doi:10.1016/j.pneurobio.2010.10.008 · Cited by 43
“This study provided the validation of zebrafish as a model to find g-secretase lowering drugs, with somitogenesis and neurogenesis readouts being present already at 24 hpf (Geling et al., 2002).”
MethodIn vitro and in vivo profiling of CHF5022 and CHF5074
Imbimbo, B. P., Giudice, E. D., Cenacchi, V., Volta, R., Villetti, G., Facchinetti, F., Riccardi, B., Puccini, P., Moretto, N., Grassi, F., et al. (2007) · Pharmacological Research · doi:10.1016/j.phrs.2006.12.010 · Cited by 43
NF-κB is required for cnidocyte development in the sea anemone Nematostella vectensis
Wolenski, F. S., Bradham, C. A., Finnerty, J. R., & Gilmore, T. D. (2012) · Developmental Biology · doi:10.1016/j.ydbio.2012.10.004 · Cited by 42
Hedgehog signaling is required for differentiation of endocardial progenitors in zebrafish
Wong, K. S., Rehn, K., Desai, S. P., Kohli, V., Hunter, W. G., Uhl, J. D., Rost, M. S., & Sumanas, S. (2011) · Developmental Biology · doi:10.1016/j.ydbio.2011.11.004 · Cited by 42
Notch Signaling Is Inactive but Inducible in Human Embryonic Stem Cells
Noggle, S., Weiler, D. A., & Condie, B. G. (2006) · Stem Cells · doi:10.1634/stemcells.2005-0314 · Cited by 41
Aster, J. C. (2005) · International Journal of Hematology · doi:10.1532/ijh97.05096 · Cited by 41
“� -Secretase cleaves many membrane proteins besides NOTCH receptors (summarized in [66]), but the developmental phenotypes produced by genetic [67] or pharmacologic loss of � -secretase function [36, 68 ,69] resemble those seen in NOTCH deficiency, suggesting that NOTCH receptors are major in vivo substrates.”
BackgroundKubo, F., & Nakagawa, S. (2009) · Development · doi:10.1242/dev.029272 · Cited by 40
“To further confirm this possibility, we prepared retinal explants and treated them with a γ-secretase inhibitor, DAPT, a potent inhibitor of the Notch signaling pathway (Geling et al., 2002).”
MethodPhenotypic analysis of images of zebrafish treated with Alzheimer's γ-secretase inhibitors
Arslanova, D., Yang, T., Xu, X., Wong, S. T. C., Augelli‐Szafran, C. E., & Xia, W. (2010) · BMC Biotechnology · doi:10.1186/1472-6750-10-24 · Cited by 40
“Similarities have been observed between DAPT-treated embryos and Notch pathway mutants, and certain phenotypes in DAPT treated embryos can be partially rescued by microinjection of NICD mRNA [ 24 ].”
BackgroundFischer, B., Metzger, M., Richardson, R., Knyphausen, P., Ramezani, T., Franzen, R., Schmelzer, E., Bloch, W., Carney, T. J., & Hammerschmidt, M. (2014) · PLoS Genetics · doi:10.1371/journal.pgen.1004048 · Cited by 40
“208255) [82], 5 mg/ml of the caspase 3 peptide inhibitor z-DEVDfmk (Calbiochem 264155-80) [83] or 0.”
Li, S., Zhang, X., Wang, Y., Ji, H., Du, Y., & Liu, H. (2012) · Neurological Sciences · doi:10.1007/s10072-012-0948-6 · Cited by 40
Petit-Paitel, A., Pasini, A., da Costa, C. A., Ayral, E., Hernandez, J., Dumanchin‐Njock, C., Phiel, C. J., Marambaud, P., Wilk, S., Farzan, M., et al. (2003) · Journal of Neuroscience Research · doi:10.1002/jnr.10747 · Cited by 39
“As shown in Figure 3B, treatment of zebrafish embryos with 50 M DAPT resulted in a clear salt-andpepper pattern of deltaC expression in 95% (19/20) of the cases, respectively, confirming that DAPT is able to block Notch signaling in vivo (Geling et al., 2002).”
Exploring stem cell biology with small molecules
Chen, S., Hilcove, S. A., & Ding, S. (2005) · Molecular BioSystems · doi:10.1039/b512000b · Cited by 39
Desmoglein 4 is regulated by transcription factors implicated in hair shaft differentiation
Bazzi, H., Demehri, S., Potter, C. S., Barber, A. G., Awgulewitsch, A., Kopan, R., & Christiano, A. M. (2009) · Differentiation · doi:10.1016/j.diff.2009.06.004 · Cited by 38
“In addition, the g-secretase inhibitor DAPT {N-(N-[3,5difluorophenacetyl]-L-alanyl)-S-phenylglycine t-butyl ester} was unable to reduce the endogenous activity of H3 in HaCaT keratinocytes (data not shown) (Geling et al., 2002).”
Salta, E., Lau, P., Sala Frigerio, C., Coolen, M., Bally-Cuif, L., & De Strooper, B. (2014) · Developmental Cell · doi:10.1016/j.devcel.2014.07.006 · Cited by 36
Self-citationFluhrer, R., Fukumori, A., Martin, L., Grammer, G., Haug‐Kröper, M., Klier, B., Winkler, E., Kremmer, E., Condron, M. M., Teplow, D. B., et al. (2008) · Journal of Biological Chemistry · doi:10.1074/jbc.m806092200 · Cited by 38
Self-citationAlaña, L., Sesé, M., Cánovas, V., Punyal, Y., Fernández, Y., Abasolo, I., de Torres, I. M., Ruiz‐Herguido, C., Espinosa, L., Bigas, A., et al. (2014) · Molecular Cancer · doi:10.1186/1476-4598-13-74 · Cited by 37
“To confirm that prostate cells have active Notch signaling [33], RWPE1 cells, derived from benign prostate epithelium, and PC-3 prostate cancer cells were treated with the γ-secretase inhibitor DAPT, known to prevent Notch processing and transcriptional signaling [48].”
BackgroundVascular Endothelial Growth Factor and Its Receptors in Embryonic Zebrafish Blood Vessel Development
Goishi, K., & Klagsbrun, M. (2004) · Current topics in developmental biology/Current Topics in Developmental Biology · doi:10.1016/s0070-2153(04)62005-9 · Cited by 37
“Notch–delta signaling is regulated by proteolytic cleavage of Notch by -secretase (Fortini, 2002; Lai, 2002) and treatment of zebrafish embryos with a -secretase inhibitor blocks Notch signaling and aVects embryonic neural development (Geling et al., 2002).”
BackgroundWrigley, J. D. J., Schurov, I., Nunn, E. J., Martin, A. C. L., Clarke, E. E., Ellis, S., Bonnert, T. P., Shearman, M. S., & Beher, D. (2004) · Journal of Biological Chemistry · doi:10.1074/jbc.m413086200 · Cited by 37
her9 promotes floor plate development in zebrafish
Latimer, A. J., Shin, J., & Appel, B. (2005) · Developmental Dynamics · doi:10.1002/dvdy.20264 · Cited by 37
“Although many vertebrate h/E(spl) genes are regulated by Notch signaling, a few, such as zebrafish her5 (Geling et al., 2003), mouse and frog Hes6 (Bae et al., 2000; Koyano-Nakagawa et al., 2000), and mouse Hes3 (Hirata et al., 2000) appear to function independently of Notch, as do hairy genes in…”
BackgroundAspartic Proteases Involved in Alzheimer's Disease
Schmidt, B. (2003) · ChemBioChem · doi:10.1002/cbic.200200532 · Cited by 38
Rigg, E., Wang, J., Xue, Z., Lunavat, T. R., Liu, G., Hoang, T., Parajuli, H., Han, M., Bjerkvig, R., Nazarov, P. V., et al. (2023) · Journal of Extracellular Vesicles · doi:10.1002/jev2.12363 · Cited by 36
Novel genes upregulated when NOTCH signalling is disrupted during hypothalamic development
Ratié, L., Ware, M., Barloy-Hubler, F., Romé, H., Gicquel, I., Dubourg, C., David, V., & Dupé, V. (2013) · Neural Development · doi:10.1186/1749-8104-8-25 · Cited by 36
“Embryos were treated with DMSO or 40 μM of DAPT in L15 culture medium (supplemented with chick serum and gentamycin).”
BackgroundInfluentialEpigenetic regulation of NOTCH1 and NOTCH3 by KMT2A inhibits glioma proliferation
Huang, Y.-C., Lin, S., Shih, H., Chou, C.-H., Chu, H.-H., Chiu, C., Yuh, C., Yeh, T., & Cheng, Y. (2017) · Oncotarget · doi:10.18632/oncotarget.18668 · Cited by 36
“DAPT inhibits γ-secretase activity and thus generally inhibits the activation of all NOTCH receptors [29].”
BackgroundBinesh, A., Devaraj, S. N., & Devaraj, H. (2018) · Biochimie · doi:10.1016/j.biochi.2018.02.011 · Cited by 36
Gourronc, F. A., Ahmad, N., Nedza, N., Eggleston, T., & Rebagliati, M. R. (2007) · Developmental Dynamics · doi:10.1002/dvdy.21249 · Cited by 36
“Treatment of zebrafish embryos with DAPT accurately phenocopies genetic mutations that block Notch signaling (Geling et al., 2002).”
BackgroundMethodStemness Enhancement of Human Neural Stem Cells following Bone Marrow MSC Coculture
Haragopal, H., Yu, D., Zeng, X., Kim, S., Han, I., Ropper, A. E., Anderson, J. E., & Teng, Y. D. (2015) · Cell Transplantation · doi:10.3727/096368915x687561 · Cited by 35
Flasse, L. C., Stern, D., Pirson, J. L., Manfroid, I., Peers, B., & Voz, M. L. (2013) · Developmental Biology · doi:10.1016/j.ydbio.2013.01.011 · Cited by 35
“with DAPT, a g-secretase inhibitor of Notch signaling pathway (Geling et al., 2002).”
BackgroundMethodInfluentialChu, J., & Praticò, D. (2012) · Journal of Neuroinflammation · doi:10.1186/1742-2094-9-127 · Cited by 35
“This observation makes any potential therapeutic application of FLAP inhibitor(s), which could act as γ-secretase modulators, in AD feasible without the potential toxicity of the classical inhibitors of the complex [26,27].”
The vexing complexity of the amyloidogenic pathway
Castro, M., Hadziselimovic, A., & Sanders, C. R. (2019) · Protein Science · doi:10.1002/pro.3606 · Cited by 40
Multiple zebrafish atoh1 genes specify a diversity of neuronal types in the zebrafish cerebellum
Kidwell, C. U., Su, C.-Y., Hibi, M., & Moens, C. B. (2018) · Developmental Biology · doi:10.1016/j.ydbio.2018.03.004 · Cited by 34
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Anti-Aβ agents for mild to moderate Alzheimer's disease: systematic review and meta-analysis
Lu, L., Zheng, X., Wang, S., Tang, C., Zhang, Y., Yao, G., Zeng, J., Ge, S., Wen, H., Xu, M., et al. (2020) · Journal of Neurology Neurosurgery & Psychiatry · doi:10.1136/jnnp-2020-323497 · Cited by 35
Song, Y., Willer, J. R., Scherer, P. C., Panzer, J. A., Kugath, A., Skordalakes, E., Gregg, R. G., Willer, G. B., & Balice‐Gordon, R. J. (2010) · PLoS ONE · doi:10.1371/journal.pone.0013743 · Cited by 34
Computerized image analysis for quantitative neuronal phenotyping in zebrafish
Liu, T., Lu, J., Wang, Y., Campbell, W. A., Huang, L., Zhu, J., Xia, W., & Wong, S. T. C. (2005) · Journal of Neuroscience Methods · doi:10.1016/j.jneumeth.2005.10.024 · Cited by 34
Canonical Notch signaling plays an instructive role in auditory supporting cell development
Campbell, D. P., Chrysostomou, E., & Doetzlhofer, A. (2016) · Scientific Reports · doi:10.1038/srep19484 · Cited by 32
“To block Notch signaling we used DAPT, a γ -secretase inhibitor (GSI), known to efficiently block Notch receptor cleavage in intact cells 17 .”
Exploring Alzheimer's Disease in Zebrafish
Xia, W. (2010) · Journal of Alzheimer s Disease · doi:10.3233/jad-2010-1412 · Cited by 37
“Specifically, the increased number of primary neurons in DAPT treated embryos can be reduced by microinjection of NICD mRNA [54].”
InfluentialThe Canonical Wnt Pathway Regulates Retinal Stem Cells/Progenitors in Concert with Notch Signaling
Das, A. V., Bhattacharya, S., Zhao, X., Hegde, G. V., Mallya, K. B., Eudy, J. D., & Ahmad, I. (2008) · Developmental Neuroscience · doi:10.1159/000178017 · Cited by 33
“DAPT attenuates Notch signaling by inhibiting -secretase-mediated generation of NICD, which is necessary for the activation of Notch target genes [ Geling et al., 2002; Bhattacharya et al., 2007].”
BackgroundJacob, J., Ribes, V., Moore, S., Constable, S. C. J., Sasai, N., Gerety, S. S., Martin, D. J., Sergeant, C. P., Wilkinson, D. G., & Briscoe, J. (2013) · Disease Models & Mechanisms · doi:10.1242/dmm.013219 · Cited by 39
“Embryos at 22 hpf were treated with a small-molecule inhibitor of Notch signalling, the γ-secretase inhibitor DAPT, which is known to have potent activity in vivo in zebrafish (Geling et al., 2002; Imbimbo, 2008).”
MethodKaufman, M. L., Park, K. U., Goodson, N., Chew, S., Bersie, S. M., Jones, K. L., Lamba, D. A., & Brzezinski, J. A. (2019) · Developmental Biology · doi:10.1016/j.ydbio.2019.05.016 · Cited by 32
Notch Signaling Functions as a Cell-Fate Switch between the Endothelial and Hematopoietic Lineages
Lee, C. Y., Vogeli, K. M., Kim, S., Chong, S., Jiang, Y., Stainier, D. Y. R., & Jin, S. (2009) · Current Biology · doi:10.1016/j.cub.2009.07.073 · Cited by 32
“Embryos were treated with 100μM DAPT (CalBiochem) as previously described[6].”
Jiao, S., Dai, W., Lu, L., Liu, Y., Zhou, J., Li, Y., Korzh, V. P., & Duan, C. (2011) · Endocrinology · doi:10.1210/en.2010-1183 · Cited by 34
“DAPT was used to inhibit Notch signaling in zebrafish (33) at the concentration of 10 M DAPT as described previously (34).”
MethodMa, X., Drannik, A. G., Jiang, F., Peterson, R., & Turnbull, J. (2016) · Neuroreport · doi:10.1097/wnr.0000000000000725 · Cited by 31
Kong, L., Hu, Y., Yao, Y., Jiao, Y., Li, S., & Yang, J. (2015) · Biological and Pharmaceutical Bulletin · doi:10.1248/bpb.b15-00142 · Cited by 31
Eye development and photoreceptor differentiation in the cephalopod Doryteuthis pealeii
Koenig, K. M., Sun, P., Meyer, E., & Gross, J. M. (2016) · Development · doi:10.1242/dev.134254 · Cited by 32
Functional studies on the role of Notch signaling in Hydractinia development
Gahan, J. M., Schnitzler, C. E., DuBuc, T. Q., Doonan, L. B., Kanska, J. E., Gornik, S. G., Barreira, S. N., Thompson, K., Schiffer, P. H., Baxevanis, A. D., et al. (2017) · Developmental Biology · doi:10.1016/j.ydbio.2017.06.006 · Cited by 31
“…the -secretase inhibitor N-[N-(3,5-difluorophenacetyl)-l-alanyl]-S- phenylglycine t-butyl ester (DAPT); this drug prevents release of the Notch intracellular domain (NICD), an essential step in activation of the pathway (Geling et al., 2002; Käsbauer et al., 2007; Micchelli et al., 2003).”
BackgroundNotch resolves mixed neural identities in the zebrafish epiphysis
Cau, E., Quillien, A., & Blader, P. (2008) · Development · doi:10.1242/dev.013482 · Cited by 31
Zebrafish as a Model Organism to Study Nanomaterial Toxicity
Jeevanandam, J., Chan, Y. S., & Danquah, M. K. (2019) · Emerging Science Journal · doi:10.28991/esj-2019-01182 · Cited by 30
“Further, zebrafish are widely used to evaluate and monitor neurogenic phenotype [65], modulatory neurotransmitter systems and behavior [66], neurogenic phenotype [65] and DJ1 expression [67].”
BackgroundRauner, G., Jin, D. X., Miller, D. H., Gierahn, T. M., Li, C. M.-C., Sokol, E. S., Feng, Y., Mathis, R. A., Love, J. C., Gupta, P. B., et al. (2021) · Nature Communications · doi:10.1038/s41467-021-27401-6 · Cited by 30
Decoupling elongation and segmentation: Notch involvement in anostracan crustacean segmentation
Williams, T. A., Blachuta, B. J., Hegna, T. A., & Nagy, L. M. (2012) · Evolution & Development · doi:10.1111/j.1525-142x.2012.00555.x · Cited by 30
“RNAi knockdown of Notch disrupts segmentation, producing a range of phenotypes including defects in the size, shape, and width of segments (Stollewerk et al. 2003; Schoppmeier and Damen 2005; Pueyo et al. 2008).”
BackgroundInfluentialNotch Signaling Maintains Neural Rosette Polarity
Main, H., Radenkovic, J., Jin, S., Lendahl, U., & Andersson, E. R. (2013) · PLoS ONE · doi:10.1371/journal.pone.0062959 · Cited by 36
Bosch, T. C. G. (2008) · Springer eBooks · doi:10.1007/978-1-4020-8274-0_3 · Cited by 30
“We treated polyps for 48–96 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).”
MethodNotch signaling regulates endocrine cell specification in the zebrafish anterior pituitary
Dutta, S., Dietrich, J. E., Westerfield, M., & Varga, Z. M. (2008) · Developmental Biology · doi:10.1016/j.ydbio.2008.04.019 · Cited by 30
“, 2001) and blocks Notch signal transduction thus leading to typical phenotypes consistent with loss of Notch signaling in zebrafish and Drosophila (Geling et al., 2002).”
BackgroundInfluentialSynthesis of biotinylated photoaffinity probes based on arylsulfonamide γ-secretase inhibitors
Fuwa, H., Hiromoto, K., Takahashi, Y., Yokoshima, S., Kan, T., Fukuyama, T., Iwatsubo, T., Tomita, T., & Natsugari, H. (2006) · Bioorganic & Medicinal Chemistry Letters · doi:10.1016/j.bmcl.2006.05.091 · Cited by 29
Small molecule screen in embryonic zebrafish using modular variations to target segmentation
Richter, S., Schulze, U., Tomančák, P., & Oates, A. C. (2017) · Nature Communications · doi:10.1038/s41467-017-01469-5 · Cited by 28
Li, I.-C., Chan, C.-T., Lu, Y., Wu, Y., Chen, Y., Li, G., Lin, C.-Y., & Hwang, S. L. (2011) · PLoS ONE · doi:10.1371/journal.pone.0020974 · Cited by 28
Choi, Y.-H., Ann, E., Yoon, J., Mo, J., Kim, M., & Park, H.-S. (2012) · Biochimica et Biophysica Acta (BBA) - Molecular Cell Research · doi:10.1016/j.bbamcr.2012.10.018 · Cited by 29
Doi, H., Iso, T., Shiba, Y., Sato, H., Yamazaki, M., Oyama, Y., Akiyama, H., Tanaka, T., Tomita, T., Arai, M., et al. (2009) · Biochemical and Biophysical Research Communications · doi:10.1016/j.bbrc.2009.02.116 · Cited by 28
Yamaguchi, M., Imai, F., Tonou‐Fujimori, N., & Masai, I. (2010) · Mechanisms of Development · doi:10.1016/j.mod.2010.03.004 · Cited by 28
Quillien, A., Blanco‐Sánchez, B., Halluin, C., Moore, J. C., Lawson, N. D., Blader, P., & Cau, E. (2011) · Development · doi:10.1242/dev.060988 · Cited by 28
“To perform DAPT treatments, embryos were raised in embryo medium containing DAPT (Calbiochem) at 100 M and DMSO (1%), as previously described (Geling et al., 2002).”
MethodControl of Neural Cell Composition in Poly(Ethylene Glycol) Hydrogel Culture with Soluble Factors
Mooney, R., Haeger, S. M., Lawal, R., Mason, M. N., Shrestha, N., Laperle, A., Bjugstad, K. B., & Mahoney, M. J. (2011) · Tissue Engineering Part A · doi:10.1089/ten.tea.2010.0654 · Cited by 29
“DAPT supplementation may be an effective approach given that, even in cell dense cultures, DAPT can inhibit the ligand-dependent, g-secretase-mediated cleavage and activation of notch receptors that is required for the onset of gliogenesis.(10,11,37,38)”
BackgroundChemical technologies for probing embryonic development
Shestopalov, I. A., & Chen, J. (2008) · Chemical Society Reviews · doi:10.1039/b703023c · Cited by 28
γ‐secretase inhibitors for the treatment of Alzheimer's disease
Wu, W., & Zhang, L. (2009) · Drug Development Research · doi:10.1002/ddr.20288 · Cited by 28
“Notch deficiency phenotypes were observed when Drosophila and zebra fish were treated with DAPT [Wolfe et al., 2001; Geling et al., 2002].”
MethodZetterberg, H., Campbell, W. A., Yang, H. W., & Xia, W. (2006) · Journal of Biological Chemistry · doi:10.1074/jbc.m512521200 · Cited by 28
A short perspective on the long road to effective treatments for Alzheimer's disease
Reynolds, D. S. (2019) · British Journal of Pharmacology · doi:10.1111/bph.14581 · Cited by 28
Yu, S., & He, J. (2019) · eLife · doi:10.7554/elife.48660 · Cited by 26
“We disturbed Notch/Delta lateral inhibition by blocking Notch signaling using LY411575, a potent inhibitor of the g-secretase complex, which acts by preventing the cleavage of NICD (Figure 5A) (Geling et al., 2002; Katz et al., 2016).”
BackgroundPierantozzi, E., Vezzani, B., Badin, M., Curina, C., Severi, F. M., Petraglia, F., Randazzo, D., Rossi, D., & Sorrentino, V. (2016) · Stem Cells and Development · doi:10.1089/scd.2015.0336 · Cited by 26
Expression of Sox4 and Sox11 is regulated by multiple mechanisms during retinal development
Usui, A., Iwagawa, T., Mochizuki, Y., Iida, A., Wegner, M., Murakami, A., & Watanabe, S. (2013) · FEBS Letters · doi:10.1016/j.febslet.2012.12.017 · Cited by 26
“The expression levels of Hes1 and Hes5, both of which are targets of Notch signaling, were significantly suppressed by DAPT treatment (Fig.”
MethodInfluentialprdm1a and olig4 act downstream of Notch signaling to regulate cell fate at the neural plate border
Hernandez‐Lagunas, L., Powell, D. R., Law, J., Grant, K. A., & Artinger, K. (2011) · Developmental Biology · doi:10.1016/j.ydbio.2011.06.005 · Cited by 26
“We confirmed that treatment with DAPT in wildtype embryos increased the total number of primary neurons, as previously reported (Geling et al., 2002).”
Evolution and Function of the Notch Signaling Pathway: An Invertebrate Perspective
Lv, Y., Pang, X., Cao, Z., Song, C., Liu, B., Wu, W., & Pang, Q. (2024) · International Journal of Molecular Sciences · doi:10.3390/ijms25063322 · Cited by 25
“…ester (DAPT) is widely used and it inhibits Notch activation by preventing the γ -secretase-mediated cleavage of Notch and release of the NICD [16]. γ -secretase is an intramembrane proteolytic complex containing four essential sub-units: the catalytic subunit presenilin (Ps), the…”
BackgroundEnvironmental and Molecular Modulation of Motor Individuality in Larval Zebrafish
Hageter, J., Waalkes, M., Starkey, J., Copeland, H., Price, H., Bays, L. D., Showman, C., Laverty, S. M., Bergeron, S. A., & Horstick, E. J. (2021) · Frontiers in Behavioral Neuroscience · doi:10.3389/fnbeh.2021.777778 · Cited by 23
“To disrupt Notch signaling, we used the specific Υ-secretase inhibitor LY411575, which blocks the activation of the Notch signaling cascade (Geling et al., 2002; Fauq et al., 2007).”
MethodWischhof, L., Lee, H., Tutas, J., Overkott, C., Tedt, E., Stork, M., Peitz, M., Brüstle, O., Ulas, T., Händler, K., et al. (2022) · The EMBO Journal · doi:10.15252/embj.2022110595 · Cited by 23
Sox10 contributes to the balance of fate choice in dorsal root ganglion progenitors
Delfino‐Machín, M., Madelaine, R., Busolin, G., Nikaido, M., Colanesi, S., Sosa, K. C., Law, E. W. P., Toppo, S., Blader, P., Tiso, N., et al. (2017) · PLoS ONE · doi:10.1371/journal.pone.0172947 · Cited by 25
“DAPT-treatment was performed according to Geling et al (2002) [57], using 100 μM DAPT in 2% DMSO in embryo medium.”
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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