The striatal kinase DCLK3 produces neuroprotection against mutant huntingtin
Open accessAbstract
The neurobiological functions of a number of kinases expressed in the brain are unknown. Here, we report new findings on DCLK3 (doublecortin like kinase 3), which is preferentially expressed in neurons in the striatum and dentate gyrus. Its function has never been investigated. DCLK3 expression is markedly reduced in Huntington's disease. Recent data obtained in studies related to cancer suggest DCLK3 could have an anti-apoptotic effect. Thus, we hypothesized that early loss of DCLK3 in Huntington's disease may render striatal neurons more susceptible to mutant huntingtin (mHtt). We discovered that DCLK3 silencing in the striatum of mice exacerbated the toxicity of an N-terminal fragment of mHtt. Conversely, overexpression of DCLK3 reduced neurodegeneration produced by mHtt. DCLK3 also produced beneficial effects on motor symptoms in a knock-in mouse model of Huntington's disease. Using different mutants of DCLK3, we found that the kinase activity of the protein plays a key role in neuroprotection. To investigate the potential mechanisms underlying DCLK3 effects, we studied the transcriptional changes produced by the kinase domain in human striatal neurons in culture. Results show that DCLK3 regulates in a kinase-dependent manner the expression of many genes involved in transcription regulation and nucleosome/chromatin remodelling. Consistent with this, histological evaluation showed DCLK3 is present in the nucleus of striatal neurons and, protein-protein interaction experiments suggested that the kinase domain interacts with zinc finger proteins, including the transcriptional activator adaptor TADA3, a core component of the Spt-ada-Gcn5 acetyltransferase (SAGA) complex which links histone acetylation to the transcription machinery. Our novel findings suggest that the presence of DCLK3 in striatal neurons may play a key role in transcription regulation and chromatin remodelling in these brain cells, and show that reduced expression of the kinase in Huntington's disease could render the striatum highly vulnerable to neurodegeneration.
The claims and statistics of this paper haven’t been checked yet.
Run the check — free, no account needed. It reads the open-access text and checks the sources it cites.
Integrity signals
Registry
Cites
Statistics
Claims the paper makes
The claims and statistics of this paper haven’t been checked yet.
Run the check — free, no account needed. It reads the open-access text and checks the sources it cites.
Claims other papers make about this one
Each is checked against this paper’s own text: does it say what the citing paper says it does?
Genes where putatively causal eQTLs captured high FINEMAP posterior probability, greater than 95%, include ACE with schizophrenia under-expression, DCLK3 with under-expression, and SNAP91 with over-expression.
“Genes where putatively causal eQTLs captured a particularly high FINEMAP PP (>95%) (Supplementary Table 17g) include ACE encoding angiotensin converting enzyme, the target of a major class of anti-hypertensive drugs (schizophrenia under-expression), DCLK3 encoding a neuroprotective kinase29(schizophrenia under-expression) and SNAP91 (discussed below; schizophrenia over-expression).”
From Mapping genomic loci implicates genes and synaptic biology in schizophrenia (2022) · cites this paper as [29]
Self-check
Percentages, sums and reported differences re-computed from the paper’s own numbers.
The self-check needs the paper’s full text.
Cites
Systematic and integrative analysis of large gene lists using DAVID bioinformatics resources
Huang, D. W., Sherman, B. T., & Lempicki, R. A. (2009) · Nature Protocols · doi:10.1038/nprot.2008.211 · Cited by 35,890 · cited 1× · see citing works
“6), Gene Set Enrichment Analysis (GSEA) software from the Broad Institute (http://www.broadinstitute. org/gsea) or online with DAVID (Huang da et al., 2009) and GREAT (McLean et al., 2010)].”
MethodMACDONALD, M. (1993) · Cell · doi:10.1016/0092-8674(93)90585-e · Cited by 8,366 · see citing works
Zhang, Y., Chen, K., Sloan, S. A., Bennett, M. L., Scholze, A. R., O'Keeffe, S., Phatnani, H. P., Guarnieri, P., Caneda, C., Ruderisch, N., et al. (2014) · The Journal of Neuroscience · doi:10.1523/jneurosci.1860-14.2014 · Cited by 5,508 · cited 1× · see citing works
“In line with this hypothesis, DCLK3 displays a more neuron-specific pattern of expression than DCLK1/2, which are also expressed in astrocytes (http://web.stanford.edu/group/barres_lab/brain_ rnaseq.html) (Zhang et al., 2014).”
BackgroundGREAT improves functional interpretation of cis-regulatory regions
McLean, C. Y., Bristor, D., Hiller, M., Clarke, S. L., Schaar, B. T., Lowe, C. B., Wenger, A. M., & Bejerano, G. (2010) · Nature Biotechnology · doi:10.1038/nbt.1630 · Cited by 4,502 · cited 2× · see citing works
“, 2009) and GREAT (McLean et al., 2010) indicated that the upregulated genes were significantly enriched in functions and pathways linked to chromatin biology and nucleosomes, whereas the downregulated genes showed no significant enrichment in any specific function or pathway (Fig.”
BackgroundMethodMaster Transcription Factors and Mediator Establish Super-Enhancers at Key Cell Identity Genes
Whyte, W. A., Orlando, D. A., Hnisz, D., Abraham, B. J., Lin, C. Y., Kagey, M. H., Rahl, P. B., Lee, T. I., & Young, R. A. (2013) · Cell · doi:10.1016/j.cell.2013.03.035 · Cited by 4,143 · cited 1× · see citing works
“, 2015), a category of enhancers controlling cell-type specific identity through epigenetic mechanisms (Whyte et al., 2013).”
BackgroundShah, M. A., Datson, N. A., Srinidhi, L., Stanton, V. P., MacDonald, M. E., Allard, M. W., Youngman, S., Am, F., Mott, R., Draths, K., et al. (1993) · Cell · Cited by 3,055 · see citing works
The MIntAct project—IntAct as a common curation platform for 11 molecular interaction databases
Orchard, S. E., Ammari, M. G., Aranda, B., Breuza, L., Briganti, L., Broackes-Carter, F. C., Campbell, N. H., Chavali, G. B., Chen, C. C. L., del‐Toro, N., et al. (2013) · Nucleic Acids Research · doi:10.1093/nar/gkt1115 · Cited by 1,835 · cited 2× · see citing works
“org) consortium through IntAct (Orchard et al., 2014) and assigned the identifier IM-26152.”
BackgroundMethodToward a functional analysis of the yeast genome through exhaustive two-hybrid screens
Fromont‐Racine, M., Rain, J., & Legrain, P. (1997) · Nature Genetics · doi:10.1038/ng0797-277 · Cited by 913 · cited 1× · see citing works
“We screened 110 million clones (11-fold coverage) by a mating approach, with YHGX13 (Y187 ade2-101::loxPkanMX-loxP, mat ) and L40 Gal4 (mata) yeast strains, as previously described (Fromont-Racine et al., 1997).”
MethodProtein interaction mapping: ADrosophilacase studyPreprint
Formstecher, É., Aresta, S., Collura, V., Hamburger, A., Meil, A., Trehin, A., Reverdy, C., Betin, V. M. S., Maire, S., Brun, C., et al. (2005) · Genome Research · doi:10.1101/gr.2659105 · Cited by 581 · cited 1× · see citing works
“A confidence score (predicted biological score) was attributed to each interaction, as previously described (Formstecher et al., 2005).”
MethodMenalled, L., Sison, J. D., Dragatsis, I., Zeitlin, S. O., & Chesselet, M. (2003) · The Journal of Comparative Neurology · doi:10.1002/cne.10776 · Cited by 528 · cited 4× · see citing works
“molecular phenotype of medium-sized spiny neurons (loss of DARPP32), we asked whether DCLK3 could produce beneficial effects on the function of striatal neurons in the KI140CAG mouse model of Huntington’s disease (Menalled et al., 2003).”
BackgroundInfluentialAurnhammer, C., Haase, M., Müther, N., Mück-Häusl, M., Rauschhuber, C., Huber, I., Nitschko, H., Busch, U., Sing, A., Ehrhardt, A., et al. (2012) · Human Gene Therapy Methods · doi:10.1089/hgtb.2011.034 · Cited by 495 · cited 1× · see citing works
“The concentration of the vector stocks was estimated by quantitative PCR as described by Aurnhammer et al. (2012) and expressed as the number of viral genomes per ml of concentrated stocks (vg/ml).”
MethodUsing the two-hybrid system to detect protein-protein interactions
Bartel, P. L., Chien, C., Sternglanz, R., & Fields, S. (1993) · doi:10.1093/oso/9780199633913.003.0007 · Cited by 429 · see citing works
Integrated genomics and proteomics define huntingtin CAG length-dependent networks in mice
Langfelder, P., Cantle, J. P., Chatzopoulou, D., Wang, N., Gao, F., Al-Ramahi, I., Lu, X.-H., Ramos, E. M., El-Zein, K., Zhao, Y., et al. (2016) · Nature Neuroscience · doi:10.1038/nn.4256 · Cited by 385 · cited 4× · see citing works
“Approximately 40% of these genes were found also to be significantly deregulated in knock-in mouse models of Huntington’s disease (Langfelder et al., 2016), suggesting a link between decreased DCLK3 and altered regulation of genes implicated in chromatin biology and transcription.”
BackgroundResultInfluentialBrouillet, E., Jacquard, C., Bizat, N., & Blum, D. L. (2005) · Journal of Neurochemistry · doi:10.1111/j.1471-4159.2005.03515.x · Cited by 361 · cited 1× · see citing works
“It has been suggested that factors selectively expressed in the striatum may render GABAergic projection neurons (medium-sized spiny neurons) particularly susceptible to degeneration (Brouillet et al., 2005; Han et al., 2010; Francelle et al., 2014).”
BackgroundSelf-citationFaideau, M., Kim, J., Cormier, K., Gilmore, R., Welch, M. J., Aurégan, G., Dufour, N., Guillermier, M., Brouillet, E., Hantraye, P., et al. (2010) · Human Molecular Genetics · doi:10.1093/hmg/ddq212 · Cited by 343 · cited 3× · see citing works
“A volume of 2ml of lentiviral or AAV suspension was injected into the mouse striatum, as described (Faideau et al., 2010), at the following stereotaxic coordinates: 1.0 mm anterior and 2.0 mm lateral to bregma, at a depth of 2.7 mm from the dura, with the tooth bar set at 0.0 mm.”
BackgroundMethodInfluentialSelf-citationRhes, a Striatal Specific Protein, Mediates Mutant-Huntingtin Cytotoxicity
Subramaniam, S., Sixt, K. M., Barrow, R. K., & Snyder, S. H. (2009) · Science · doi:10.1126/science.1172871 · Cited by 340 · cited 3× · see citing works
“For example, dopamine and its subtype 2 membrane receptors (D2R), PDE10a, and the small GTPase Rhes have been shown to be preferentially expressed in the striatum, have early reduction of their expression in Huntington’s disease patients and Huntington’s disease models and have been shown to render striatal neurons hi…”
BackgroundKuhn, A., Goldstein, D. R., Hodges, A., Strand, A. D., Sengstag, T., Kooperberg, C. L., Bečanović, K., Pouladi, M. A., Sathasivam, K., Cha, J.-H. J., et al. (2007) · Human Molecular Genetics · doi:10.1093/hmg/ddm133 · Cited by 327 · cited 4× · see citing works
“This signature is characterized by enrichment in genes associated with biological functions linked to neuronal activity (Kuhn et al., 2007; Seredenina and Luthi-Carter, 2012; Achour et al., 2015).”
BackgroundInfluential[34] Ras-Raf interaction: Two-hybrid analysis
Vojtek, A. B., & Hollenberg, S. M. (1995) · Methods in enzymology on CD-ROM/Methods in enzymology · doi:10.1016/s0076-6879(95)55036-4 · Cited by 293 · cited 1× · see citing works
“The pB29 and pP6 constructs were derived from the original pBTM116 (Vojtek and Hollenberg, 1995; Beranger et al., 1997) and pGADGH (Bartel et al., 1993) plasmids, respectively.”
Methodde Almeida, L. P., Ross, C. A., Zala, D., Aebischer, P., & Déglon, N. (2002) · Journal of Neuroscience · doi:10.1523/jneurosci.22-09-03473.2002 · Cited by 226 · cited 1× · see citing works
“…and administration DNA sequences encoding green fluorescent protein (GFP) and C-terminally haemagglutinin (HA)-tagged mouse short and long forms of DCLK3 were inserted into the SIN-W-PGK lentiviral vector (de Almeida et al., 2002) to generate LV-GFP, LV-S-rDCLK3-HA and LV-L-rDCLK3-HA, respectively.”
MethodSelf-citationOhmae, E., Ouchi, Y., Oda, M., Suzuki, T., Nobesawa, S., Kanno, T., Yoshikawa, E., Futatsubashi, M., Ueda, Y., Okada, H., et al. (2005) · NeuroImage · doi:10.1016/j.neuroimage.2005.08.008 · Cited by 222 · cited 1× · see citing works
“DCLK3 is the third member of the doublecortin-like kinase (DCLK) family (Ohmae et al., 2006b).”
BackgroundWang, Y., Faiola, F., Xu, M., Pan, S., & Martinez, E. (2008) · Journal of Biological Chemistry · doi:10.1074/jbc.m806936200 · Cited by 218 · cited 1× · see citing works
“Like TADA3, SUPT3H is a core component of the SAGA complex (Wang et al., 2008).”
BackgroundSustained effects of nonallele‐specific Huntingtin silencing
Drouet, V., Perrin, V., Hässig, R., Dufour, N., Aurégan, G., Alves, S., Bonvento, G., Brouillet, E., Luthi‐Carter, R., Hantraye, P., et al. (2009) · Annals of Neurology · doi:10.1002/ana.21569 · Cited by 217 · cited 1× · see citing works
“We inserted short hairpin RNAs (shRNAs) targeting mouse DCLK3 (target sequence: 50 GAGAAGTGTAAGAGAGAAA 3’) and luciferase (target sequence: 50 CGTACGCGGAA TACTTCGA 30) into a bicistronic lentiviral vector (Drouet et al., 2009), such that the infected cells expressed the reporter protein GFP.”
MethodSelf-citationBonnet, J., Wang, C., Baptista, T., Vincent, S. D., Hsiao, W.-C., Stierlé, M., Kao, C.-F., Tora, L., & Devys, D. (2014) · Genes & Development · doi:10.1101/gad.250225.114 · Cited by 213 · cited 1× · see citing works
“SAGA plays a key role in transcription, regulating the transcription of almost all genes in yeast and human cells (Bonnet et al., 2014).”
BackgroundHottinger, A. F., Azzouz, M., Déglon, N., Aebischer, P., & Zurn, A. D. (2000) · Journal of Neuroscience · doi:10.1523/jneurosci.20-15-05587.2000 · Cited by 189 · cited 1× · see citing works
“Lentiviral particles were produced as previously described (Hottinger et al., 2000).”
MethodSelf-citationGiampà, C., Laurenti, D., Anzilotti, S., Bernardi, G., Menniti, F. S., & Fusco, F. R. (2010) · PLoS ONE · doi:10.1371/journal.pone.0013417 · Cited by 184 · cited 1× · see citing works
“…in the striatum, have early reduction of their expression in Huntington’s disease patients and Huntington’s disease models and have been shown to render striatal neurons highly vulnerable to mHtt (Charvin et al., 2005, 2008; Benchoua et al., 2008; Subramaniam et al., 2009; Giampa et al., 2010).”
BackgroundActivin A directs striatal projection neuron differentiation of human pluripotent stem cells
Arber, C., Precious, S. V., Cambray, S., Risner-Janiczek, J. R., Kelly, C. M., Noakes, Z., Fjodorova, M., Heuer, A., Ungless, M. A., Rodríguez, T. A., et al. (2015) · Development · doi:10.1242/dev.117093 · Cited by 183 · cited 1× · see citing works
“Striatal neuron progenitors were derived from human embryonic stem cells as previously described (Nicoleau et al., 2013; Arber et al., 2015).”
MethodHan, I., You, Y., Kordower, J. H., Brady, S. T., & Morfini, G. A. (2010) · Journal of Neurochemistry · doi:10.1111/j.1471-4159.2010.06672.x · Cited by 171 · cited 1× · see citing works
“It has been suggested that factors selectively expressed in the striatum may render GABAergic projection neurons (medium-sized spiny neurons) particularly susceptible to degeneration (Brouillet et al., 2005; Han et al., 2010; Francelle et al., 2014).”
BackgroundWhat have we learned from gene expression profiles in Huntington's disease?
Seredenina, T. S., & Luthi‐Carter, R. (2011) · Neurobiology of Disease · doi:10.1016/j.nbd.2011.07.001 · Cited by 149 · cited 2× · see citing works
“This signature is characterized by enrichment in genes associated with biological functions linked to neuronal activity (Kuhn et al., 2007; Seredenina and Luthi-Carter, 2012; Achour et al., 2015).”
BackgroundShu, T., Tseng, H.-C., Sapir, T., Stern, P., Zhou, Y., Sanada, K., Fischer, A., Coquelle, F. M., Reiner, O., & Tsai, L. (2006) · Neuron · doi:10.1016/j.neuron.2005.10.039 · Cited by 145 · cited 1× · see citing works
“Similarly, DCLK1/2 can regulate the spindle orientation of neuronal precursors during mitosis and cortical development independently of kinase activity (Shu et al., 2006).”
BackgroundCharvin, D., Vanhoutte, P., Pagès, C., Borelli, E., & Caboche, J. (2005) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.0502698102 · Cited by 136 · see citing works
Doublecortin-like kinase enhances dendritic remodelling and negatively regulates synapse maturation
Shin, E., Kashiwagi, Y., Kuriu, T., Iwasaki, H., Tanaka, T., Koizumi, H., Gleeson, J. G., & Okabe, S. (2013) · Nature Communications · doi:10.1038/ncomms2443 · Cited by 134 · cited 3× · see citing works
“including the organization of dendritic spines in particular (Kerjan et al., 2009; Shin et al., 2013) and play an important role in axonal regeneration mainly through their DCX domain (Nawabi et al.”
BackgroundPathophysiology of Huntingtonʼs disease: from huntingtin functions to potential treatments
Roze, E. F., Saudou, F., & Caboche, J. (2008) · Current Opinion in Neurology · doi:10.1097/wco.0b013e328304b692 · Cited by 127 · cited 1× · see citing works
“It also causes changes in the cytoskeletonmediated transport machinery (Hinckelmann et al., 2013), and defects in signalling pathways involved in cell survival (Roze et al., 2008).”
BackgroundSelf-citationFunctions of SAGA in development and disease
Wang, L., & Dent, S. (2014) · Epigenomics · doi:10.2217/epi.14.22 · Cited by 127 · see citing works
Nawabi, H., Belin, S., Cartoni, R., Williams, P. R., Wang, C., Latrémolière, A., Wang, X., Zhu, J., Taub, D. G., Fu, X., et al. (2015) · Neuron · doi:10.1016/j.neuron.2015.10.005 · Cited by 117 · see citing works
Nicoleau, C., Varela, C., Bonnefond, C., Maury, Y., Bugi, A., Aubry, L., Viegas, P., Bourgois-Rocha, F., Peschanski, M., & Perrier, A. L. (2013) · Stem Cells · doi:10.1002/stem.1462 · Cited by 107 · cited 1× · see citing works
“Striatal neuron progenitors were derived from human embryonic stem cells as previously described (Nicoleau et al., 2013; Arber et al., 2015).”
MethodSelf-citationAchour, M., Gras, S. L., Keime, C., Parmentier, F., Lejeune, F., Boutillier, A., Néri, C., Davidson, I., & Mérienne, K. (2015) · Human Molecular Genetics · doi:10.1093/hmg/ddv099 · Cited by 99 · cited 4× · see citing works
“The genes downregulated in Huntington’s disease striatum have been shown to be regulated by super-enhancers (Achour et al., 2015), a category of enhancers controlling cell-type specific identity through epigenetic mechanisms (Whyte et al.”
BackgroundInfluentialZuccato, C., & Cattaneo, E. F. (2014) · Handbook of experimental pharmacology · doi:10.1007/978-3-642-45106-5_14 · Cited by 92 · see citing works
Berger, A., Lorain, S., Joséphine, C., Desrosiers, M., Peccate, C., Voït, T., Garcı́a, L., Sahel, J., & Bemelmans, A. (2015) · Molecular Therapy · doi:10.1038/mt.2015.11 · Cited by 88 · cited 1× · see citing works
“All constructs were packaged into AAVrh10 capsids by the MIRCen viral production platform, as previously described (Berger et al., 2015).”
MethodSelf-citationIn vivo imaging of brain glutamate defects in a knock-in mouse model of Huntington's disease
Pépin, J., Francelle, L., Sauvage, M.-A. C.-D., de Longprez, L., Gipchtein, P., Cambon, K., Valette, J., Brouillet, E., & Flament, J. (2016) · NeuroImage · doi:10.1016/j.neuroimage.2016.06.023 · Cited by 87 · cited 1× · see citing works
“We therefore investigated whether the restoration of DCLK3 expression in the striatum of these mice could improve their well-characterized Huntington’s disease behavioural phenotype (Menalled et al., 2003; Pepin et al., 2016).”
BackgroundSelf-citationKerjan, G., Koizumi, H., Han, E. B., Dubé, C. M., Djakovic, S. N., Patrick, G. N., Baram, T. Z., Heinemann, S. F., & Gleeson, J. G. (2009) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.0812687106 · Cited by 86 · cited 2× · see citing works
“including the organization of dendritic spines in particular (Kerjan et al., 2009; Shin et al., 2013) and play an important role in axonal regeneration mainly through their DCX domain (Nawabi et al.”
BackgroundReleasing the brake: restoring fast axonal transport in neurodegenerative disorders
Hinckelmann, M.-V., Zala, D., & Saudou, F. (2013) · Trends in Cell Biology · doi:10.1016/j.tcb.2013.08.007 · Cited by 78 · cited 1× · see citing works
“It also causes changes in the cytoskeletonmediated transport machinery (Hinckelmann et al., 2013), and defects in signalling pathways involved in cell survival (Roze et al., 2008).”
BackgroundSelf-citationBenchoua, A., Trioulier, Y., Diguet, E., Malgorn, C., Gaillard, M., Dufour, N., Elalouf, J., Krajewski, S., Hantraye, P., Déglon, N., et al. (2008) · Human Molecular Genetics · doi:10.1093/hmg/ddn033 · Cited by 72 · cited 3× · see citing works
“Primary cultures of striatal neurons were set up and maintained as previously described (Benchoua et al., 2008).”
BackgroundMethodSelf-citationContribution of Neuroepigenetics to Huntington’s Disease
Francelle, L., Lotz, C., Outeiro, T. F., Brouillet, E., & Mérienne, K. (2017) · Frontiers in Human Neuroscience · doi:10.3389/fnhum.2017.00017 · Cited by 69 · cited 1× · see citing works
“Transcriptomic studies of the striatum in mouse models of Huntington’s disease and Huntington’s disease patients have identified a functional signature associated with downregulated genes (Francelle et al., 2017).”
BackgroundSelf-citationLiu, N. Q., ter Huurne, M., Nguyen, L. N. M., Peng, T., Wang, S.-Y., Studd, J. B., Joshi, O., Ongen, H., Bramsen, J. B., Yan, J., et al. (2017) · Nature Communications · doi:10.1038/ncomms14418 · Cited by 67 · cited 2× · see citing works
“This suggested that DCLK3 has biological functions that may modulate cell survival (Liu et al., 2017).”
BackgroundHaloperidol protects striatal neurons from dysfunction induced by mutated huntingtin in vivo
Charvin, D., Roze, E. F., Perrin, V., Deyts, C., Bétuing, S., Pagès, C., Régulier, E., Luthi‐Carter, R., Brouillet, E., Déglon, N., et al. (2007) · Neurobiology of Disease · doi:10.1016/j.nbd.2007.07.028 · Cited by 59 · cited 1× · see citing works
“…in the striatum, have early reduction of their expression in Huntington’s disease patients and Huntington’s disease models and have been shown to render striatal neurons highly vulnerable to mHtt (Charvin et al., 2005, 2008; Benchoua et al., 2008; Subramaniam et al., 2009; Giampa et al., 2010).”
BackgroundSelf-citationBéranger, F. (1997) · Nucleic Acids Research · doi:10.1093/nar/25.10.2035 · Cited by 58 · cited 2× · see citing works
“The pB29 and pP6 constructs were derived from the original pBTM116 (Vojtek and Hollenberg, 1995; Beranger et al., 1997) and pGADGH (Bartel et al.”
MethodOhmae, S., Takemoto‐Kimura, S., Okamura, M., Adachi-Morishima, A., Nonaka, M., Fuse, T., Kida, S., Tanji, M., Furuyashiki, T., Arakawa, Y., et al. (2006) · Journal of Biological Chemistry · doi:10.1074/jbc.m513212200 · Cited by 55 · cited 1× · see citing works
“DCLK3 is the third member of the doublecortin-like kinase (DCLK) family (Ohmae et al., 2006b).”
BackgroundFrancelle, L., Galvan, L., Gaillard, M., Petit, F., Bernay, B., Guillermier, M., Bonvento, G., Dufour, N., Elalouf, J., Hantraye, P., et al. (2014) · Neurobiology of Aging · doi:10.1016/j.neurobiolaging.2014.11.014 · Cited by 52 · cited 4× · see citing works
“Tissue processing and western blotting Primate tissue and fractionation experiments For biochemical studies, we used control frozen macaque (M. fascicularis) brain samples, as previously described (Francelle et al., 2015a).”
BackgroundMethodInfluentialSelf-citationBurgess, H. A., & Reiner, O. (2001) · Journal of Biological Chemistry · doi:10.1074/jbc.m105153200 · Cited by 51 · cited 7× · see citing works
“DCLK1 and DCLK2 are involved in neural development and the maturation of neuronal architecture, including the organization of dendritic spines in particular (Kerjan et al., 2009; Shin et al., 2013) and play an important role in axonal regeneration mainly through their DCX domain (Nawabi et al., 2015).”
BackgroundInfluentialBrochier, C., Gaillard, M., Diguet, E., Caudy, N., Dossat, C., Segurens, B., Wincker, P., Roze, E. F., Caboche, J., Hantraye, P., et al. (2008) · Physiological Genomics · doi:10.1152/physiolgenomics.00125.2007 · Cited by 47 · cited 7× · see citing works
“Furthermore, an analysis of the expression of the genes encoding these seven interactors in the brain based on previously reported mouse SAGE data (Brochier et al., 2008), or more recent region- and cell type-specific transcriptomic databases (http://mouse.”
BackgroundMethodResultInfluentialSelf-citationFrancelle, L., Galvan, L., & Brouillet, E. (2014) · Frontiers in Cellular Neuroscience · doi:10.3389/fncel.2014.00295 · Cited by 41 · cited 1× · see citing works
“It has been suggested that factors selectively expressed in the striatum may render GABAergic projection neurons (medium-sized spiny neurons) particularly susceptible to degeneration (Brouillet et al., 2005; Han et al., 2010; Francelle et al., 2014).”
BackgroundSelf-citationNormal Aging Modulates the Neurotoxicity of Mutant Huntingtin
Diguet, E., Petit, F., Escartin, C., Cambon, K., Bizat, N., Dufour, N., Hantraye, P., Déglon, N., & Brouillet, E. (2009) · PLoS ONE · doi:10.1371/journal.pone.0004637 · Cited by 39 · cited 2× · see citing works
“The lentiviral vectors expressing a wild-type Htt fragment (LV-Htt171-18Q), a mutant Htt fragment (LV-Htt171-82Q) or beta-galactosidase (LV-bgal) have been described elsewhere (Diguet et al., 2009; Faideau et al., 2010).”
BackgroundMethodSelf-citationQuantitative Assessment of Transcriptome Differences Between Brain TerritoriesPreprint
de Chaldée, M., Gaillard, M., Bizat, N., Buhler, J., Manzoni, O. J., Bockaert, J., Hantraye, P., Brouillet, E., & Elalouf, J. (2003) · Genome Research · doi:10.1101/gr.1173403 · Cited by 37 · cited 1× · see citing works
“We previously performed a transcriptome SAGE (serial analysis of gene expression) analysis of different regions of the mouse brain, which identified about 120 genes preferentially expressed in the striatum (de Chaldee et al., 2003; Brochier et al., 2008).”
MethodSelf-citationFrancelle, L., Galvan, L., Gaillard, M., Guillermier, M., Houitte, D., Bonvento, G., Petit, F., Jan, C., Dufour, N., Hantraye, P., et al. (2014) · Human Molecular Genetics · doi:10.1093/hmg/ddu571 · Cited by 37 · cited 4× · see citing works
“Tissue processing and western blotting Primate tissue and fractionation experiments For biochemical studies, we used control frozen macaque (M. fascicularis) brain samples, as previously described (Francelle et al., 2015a).”
BackgroundMethodInfluentialSelf-citationViral-mediated overexpression of mutant huntingtin to model HD in various species
Ruiz, M., & Déglon, N. (2011) · Neurobiology of Disease · doi:10.1016/j.nbd.2011.08.023 · Cited by 27 · see citing works
Self-citationNagamine, T., Nomada, S., Onouchi, T., Kameshita, I., & Sueyoshi, N. (2014) · Biochemical and Biophysical Research Communications · doi:10.1016/j.bbrc.2014.02.075 · Cited by 15 · cited 1× · see citing works
“This finding is reminiscent of the reported migration of DCLK2 to the nucleus after the cleavage of a short C-terminal domain (Nagamine et al., 2014).”
BackgroundCapucin does not modify the toxicity of a mutant Huntingtin fragment in vivo
Galvan, L., Lepejová, N., Gaillard, M., Malgorn, C., Guillermier, M., Houitte, D., Bonvento, G., Petit, F., Dufour, N., Héry, P., et al. (2012) · Neurobiology of Aging · doi:10.1016/j.neurobiolaging.2012.01.009 · Cited by 14 · cited 1× · see citing works
“…found in the Huntington’s disease striatum could lead to a loss of function rendering striatal cells more vulnerable [e.g. the long non-coding RNA Abhd11os or Crym (Francelle et al., 2015a, c)] while in others, it might have no major impact on neurodegeneration (e.g. capucin) (Galvan et al., 2012).”
BackgroundSelf-citationKuribara, M., Jenks, B. G., Dijkmans, T. F., de Gouw, D., Ouwens, D. T. W. M., Roubos, E. W., Vreugdenhil, E., & Scheenen, W. J. J. M. (2011) · Endocrinology · doi:10.1210/en.2011-0067 · Cited by 7 · cited 7× · see citing works
“DCLK1 and DCLK2 are involved in neural development and the maturation of neuronal architecture, including the organization of dendritic spines in particular (Kerjan et al., 2009; Shin et al., 2013) and play an important role in axonal regeneration mainly through their DCX domain (Nawabi et al., 2015).”
BackgroundInfluential
Flagged first, then by citations
Research works printed but not linked: 2
- Francelle L, Galvan L, Gaillard MC, Guillermier M, Houitte D, Bonvento G, Loss of the thyroid hormone-binding protein Crym renders striatal neurons more vulnerable to mutant huntingtin in Huntington's disease. Hum Mol Genet 2015b; 24: 1563– 73. 25398949 PMC4381754
- Francelle L, Galvan L, Gaillard MC, Petit F, Bernay B, Guillermier M, The striatal long noncoding RNA Abhd11os is neuroprotective against an N-terminal fragment of mutant huntingtin in vivo. Neurobiol Aging 2015d; 36: 1601.e7– 16. 25619660
Cited by
Sorted by citations
Mapping genomic loci implicates genes and synaptic biology in schizophrenia
Trubetskoy, V., Pardiñas, A. F., Qi, T., Panagiotaropoulou, G., Awasthi, S., Bigdeli, T. B., Bryois, J., Chen, C.-Y., Dennison, C. A., Hall, L. S., et al. (2022) · Nature · doi:10.1038/s41586-022-04434-5 · Cited by 2,964 · see citing works
Inhibition of HDAC6 activity protects dopaminergic neurons from alpha-synuclein toxicity
Francelle, L., Outeiro, T. F., & Rappold, G. (2020) · Scientific Reports · doi:10.1038/s41598-020-62678-5 · Cited by 60 · see citing works
Self-citationComplementarity of gluCEST and 1H‐MRS for the study of mouse models of Huntington's disease
Pépin, J., de Longprez, L., Trovero, F., Brouillet, E., Valette, J., & Flament, J. (2020) · NMR in Biomedicine · doi:10.1002/nbm.4301 · Cited by 24 · see citing works
“The levels of these markers have also been found to be reduced in post-mortem samples in HD patients.(36) In spite of the absence of neuronal loss at 12 months, both models showed behavioral phenotypes.”
BackgroundSelf-citationCresto, N., Gaillard, M., Gardier, C., Gubinelli, F., Diguet, E., Bellet, D., Legroux, L., Mitja, J., Aurégan, G., Guillermier, M., et al. (2019) · Neurobiology of Disease · doi:10.1016/j.nbd.2019.104614 · Cited by 24 · see citing works
“Characterization of LVs-induced transduction in the rat substantia nigra LVs with the VSV-G envelope and coding for proteins under the control of PGK promoter are known to almost exclusively express transgenes in neuronal cells in the brain (Francelle et al., 2015; Galvan et al., 2018).”
BackgroundMethodSelf-citationDai, W.-J., Chen, H., & Chen, C. Y. (2018) · Evidence-based Complementary and Alternative Medicine · doi:10.1155/2018/6020197 · Cited by 19 · see citing works
Cirnaru, M., Song, S., Tshilenge, K., Corwin, C., Mleczko, J., Aguirre, C. G., Benlhabib, H., Bendl, J. M., Apontes, P., Fullard, J. F., et al. (2021) · eLife · doi:10.7554/elife.65979 · Cited by 18 · see citing works
Levchenko, А., Kanapin, A. A., Samsonova, A. A., Fedorenko, O. Y., Kornetova, E. G., Nurgaliev, T., Mazo, G. E., Semke, A. V., Kibitov, A. O., Bokhan, N. A., et al. (2020) · Progress in Neuro-Psychopharmacology and Biological Psychiatry · doi:10.1016/j.pnpbp.2020.110134 · Cited by 16 · see citing works
Royer, M., Pai, B., Menon, R., Bludau, A., Gryksa, K., Perry, R. B., Ulitsky, I., Meister, G., & Neumann, I. D. (2022) · Molecular Psychiatry · doi:10.1038/s41380-022-01481-2 · Cited by 16 · see citing works
Mechanistic and evolutionary insights into isoform-specific ‘supercharging’ in DCLK family kinases
Venkat, A., Watterson, G., Byrne, D. P., O’Boyle, B. M., Shrestha, S., Gravel, N., Fairweather, E. E., Daly, L. A., Bunn, C., Yeung, W., et al. (2023) · eLife · doi:10.7554/elife.87958 · Cited by 14 · see citing works
“DCLKs have garnered much interest as disease biomarkers, since they are upregulated in a variety of cancer pathologies ( Cheng et al., 2022a ; Gao et al., 2016 ; Westphalen et al., 2017 ), as well as neurodegenerative disorders such as Huntington’s disease ( Galvan et al., 2018 ).”
BackgroundCresto, N., Gardier, C., Gaillard, M., Gubinelli, F., Roost, P., Molina, D., Joséphine, C., Dufour, N., Aurégan, G., Guillermier, M., et al. (2021) · International Journal of Molecular Sciences · doi:10.3390/ijms22136760 · Cited by 12 · see citing works
Self-citationYu, X., Hu, X., Wan, X., Zhang, Z., Wan, X., Cai, M., Yu, T., & Xiao, J. (2025) · The American Journal of Human Genetics · doi:10.1016/j.ajhg.2024.12.018 · Cited by 12 · see citing works
CRISPR/Cas-Based Approaches to Study Schizophrenia and Other Neurodevelopmental Disorders
Kurishev, A. O., Karpov, D. S., Nadolinskaia, N. I., Гончаренко, А. В., & Голимбет, В. Е. (2022) · International Journal of Molecular Sciences · doi:10.3390/ijms24010241 · Cited by 13 · see citing works
Traunmüller, L., Duffy, E. E., Liu, H., Sanalidou, S., Krüttner, S., Assad, E. G., Sun, S., Pajarillo, N. S., Niu, N., Griffith, E. C., et al. (2025) · Nature Communications · doi:10.1038/s41467-025-63029-6 · Cited by 10 · see citing works
Cheng, J., Tang, Y. C., Dong, Y., Qin, R. L., & Dong, Z. Q. (2023) · Irish Journal of Medical Science (1971 -) · doi:10.1007/s11845-023-03430-6 · Cited by 9 · see citing works
Genomic regulatory sequences in the pathogenesis of bipolar disorder
Levchenko, А., & Plotnikova, M. (2023) · Frontiers in Psychiatry · doi:10.3389/fpsyt.2023.1115924 · Cited by 8 · see citing works
“DCLK3 that codes for Doublecortin Like Kinase 3 is expressed in the striatum and hippocampus; it is involved in regulation of transcription and has a neuroprotective role (53).”
BackgroundGuo, Y., Shen, X., Hou, X., Ou, Y., Huang, Y., Dong, Q., Tan, L., & Yu, J. (2020) · NeuroImage Clinical · doi:10.1016/j.nicl.2020.102209 · Cited by 8 · see citing works
“The kinase that DCLK3 expressed is preferentially distributed in neurons of the striatum and dentate gyrus, and DCLK3 may produce neuroprotection against Huntington's disease (Galvan et al., 2018).”
BackgroundNiewiadomska-Cimicka, A., Hache, A., Gras, S. L., Keime, C., Ye, T., Eisenmann, A., Harichane, I., Roux, M. J., Messaddeq, N., Clérin, E., et al. (2022) · Journal of Biomedical Science · doi:10.1186/s12929-022-00892-1 · Cited by 7 · see citing works
“Furthermore, Galvan et al. [101] recently showed that doublecortin like kinase 3 (DCLK3) provides neuroprotection against striatal degeneration in HD, and hypothesized that DLCK3 may play a role in the transcriptional regulation of striatal genes via its interaction with ADA3, a SAGA subunit…”
Mechanistic and evolutionary insights into isoform-specific ‘supercharging’ in DCLK family kinasesPreprint
Venkat, A., Watterson, G., Byrne, D. P., O’Boyle, B. M., Shrestha, S., Gravel, N., Fairweather, E. E., Daly, L. A., Bunn, C., Yeung, W., et al. (2023) · bioRxiv (Cold Spring Harbor Laboratory) · doi:10.1101/2023.03.29.534689 · Cited by 6 · see citing works
“DCLKs have garnered much interest as disease biomarkers, since they are upregulated in a variety of cancer pathologies (10–12), as well as neurodegenerative disorders such as Huntington’s Disease (13).”
BackgroundJarrige, M., Polvèche, H., Carteron, A., Janczarski, S., Peschanski, M., Auboeuf, D., & Martinat, C. (2021) · iScience · doi:10.1016/j.isci.2021.102767 · Cited by 5 · see citing works
Self-citationYang, H., Li, Y., Li, X., Yan, Q.-M., Han, X.-Z., Cao, J., Sang, H.-P., & Li, J. (2023) · EXPERIMENTAL ANIMALS · doi:10.1538/expanim.23-0041 · Cited by 5 · see citing works
“Moreover, BNIPL could interact with anti-apoptotic protein BCL-2 and decreased BniPL expression inhibited cell apoptosis [46, 47]. and DCLK3 was proven to have a neuroprotective effect on Huntington’s disease-related neurodegeneration [48].”
Loss of the neuronal kinase DCLK3 leads to anxiety-like behaviour and memory deficits
de Longprez, L., Gaillard, M., Decraene, C., Pérot, J., Keime, C., Nadkarni, N. A., Louçã, M., Jan, C., Liot, G., Aurégan, G., et al. (2025) · Brain · doi:10.1093/brain/awaf042 · Cited by 5 · see citing works
Self-citationNguyen, H. P., Chan, C. S. Y., Cintrón, D. L., Sheng, R. R., Harshman, L., Nobuhara, M., Ushiki, A., Biellak, C., An, K., Gordon, G., et al. (2022) · bioRxiv (Cold Spring Harbor Laboratory) · doi:10.1101/2022.11.06.515311 · Cited by 4 · see citing works
Lu, J. D., Zhao, P., Prasad, A., Gupta, N., Gravel, N., Shidhaye, T., Wells, L., Katiyar, S., & Kannan, N. (2025) · Journal of Biological Chemistry · doi:10.1016/j.jbc.2025.110664 · Cited by 3 · see citing works
“Due to the clinical significance of DCLK1, several studies have sought to investigate the physiological relevance of DCLK3 (14–17), associating it with neuroprotection in Huntington’s disease mice (14) and colo-rectal cancer progression (17).”
Jo, D., Arjunan, A., Choi, S., Jung, Y. S., Park, J., Jo, J., Kim, O. Y., & Song, J. (2023) · Food & Function · doi:10.1039/d3fo03451h · Cited by 3 · see citing works
Ahn, I., Chang, S., Lee, J., Choi, S. H., Han, J., & Kim, Y. (2025) · Advanced Science · doi:10.1002/advs.202508383 · Cited by 2 · see citing works
From heterogeneity to hope: emerging markers in triple-negative breast cancer research
Krakhmal, N. V., Taranenko, M. I., Naumov, S. S., & Vtorushin, S. V. (2025) · Medical Oncology · doi:10.1007/s12032-025-02906-y · Cited by 1 · see citing works
“Galvan L. et al. showed that DCLK3 is expressed in neurons of the striatum and dentate gyrus and that its expression is reduced during Huntington’s disease progression, suggesting a potential neuroprotective role for DCLK3 [71].”
Hu, K., Wang, Y., Xu, P., Jing, T., Cheng, X., Shen, P., Wang, B., Fu, K., Zhang, M., Gao, M., et al. (2026) · Journal of Medicinal Chemistry · doi:10.1021/acs.jmedchem.5c03183 · Cited by 1 · see citing works
Mechanistic and evolutionary insights into isoform-specific ‘supercharging’ in DCLK family kinases
Venkat, A., Watterson, G., Byrne, D. P., O’Boyle, B. M., Shrestha, S., Gravel, N., Fairweather, E. E., Daly, L. A., Bunn, C., Yeung, W., et al. (2023) · eLife · doi:10.7554/elife.87958.3 · Cited by 1 · see citing works
Zhang, T., Wang, W., Liu, T. J., Lu, S., Bian, Y.-C., Xiao, R., & Zhang, C. L. (2022) · Biological and Pharmaceutical Bulletin · doi:10.1248/bpb.b22-00184 · Cited by 1 · see citing works
Mechanistic and evolutionary insights into isoform-specific ‘supercharging’ in DCLK family kinasesPreprint
Venkat, A., Watterson, G., Byrne, D. P., O’Boyle, B. M., Shrestha, S., Gravel, N., Fairweather, E. E., Daly, L. A., Bunn, C., Yeung, W., et al. (2023) · eLife · doi:10.7554/elife.87958.1 · Cited by 1 · see citing works
Mechanistic and evolutionary insights into isoform-specific ‘supercharging’ in DCLK family kinasesPreprint
Venkat, A., Watterson, G., Byrne, D. P., O’Boyle, B. M., Shrestha, S., Gravel, N., Fairweather, E. E., Daly, L. A., Bunn, C., Yeung, W., et al. (2023) · eLife · doi:10.7554/elife.87958.2 · Cited by 1 · see citing works
Cresto, N., Gardier, C., Gaillard, M., Gubinelli, F., Roost, P., Molina, D., Joséphine, C., Dufour, N., Aurégan, G., Guillermier, M., et al. (2020) · doi:10.21203/rs.3.rs-24218/v1
“Lentiviral vectors were injected into the striatum of wildtype mice to produce local cell loss within the six weeks following transduction, as previously described [31, 32].”
MethodSelf-citationCresto, N., Gardier, C., Gaillard, M., Gubinelli, F., Roost, P., Molina, D., Joséphine, C., Dufour, N., Aurégan, G., Guillermier, M., et al. (2020) · doi:10.21203/rs.3.rs-24218/v2
Self-citationGenomic Diversity and Selection Signatures for Zaosheng CattlePreprint
Wang, Y., Xu, J., Shi, F., Guo, H., Gao, B., Yang, J., Gu, L., Yang, D., Zhang, F., Gao, D., et al. (2025) · Research Square · doi:10.21203/rs.3.rs-6059907/v1
Genomic Diversity and Selection Signatures for Zaosheng Cattle
Xu, J., Wang, Y., Shi, F., Guo, H., Gao, B., Yang, J., Gu, L., Yang, D., Zhang, F., Gao, D., et al. (2025) · Biology · doi:10.3390/biology14060623
“DCLK3 [36] was found to be involved in heat stress.”
Krakhmal, N. V., Taranenko, M. I., Naumov, S. S., & Vtorushin, S. V. (2025) · Russian Journal of Archive of Pathology · doi:10.17116/patol20258703188
Arrieta, M., Farina, F., Aboy, T. M., Mair, M. L., Mendoza, C., Tran, H., Aaronson, J., Rosinski, J., Ellerby, L., Brouillet, E., et al. (2025) · bioRxiv (Cold Spring Harbor Laboratory) · doi:10.64898/2025.12.12.693965
Self-citationde Longprez, L. (2018) · theses.fr (ABES) · doi:10.70675/9c720f01z8077z49d5z9df8z8e7cc0c69a1a
The role of the serum response factor in the pathogenesis of Huntington's disease
Awada, A. (2021) · theses.fr (ABES) · doi:10.70675/fabef4b5z9d78z440bz99f2z9be7d0814a03
Lü, Y., Han, Y., Ji, J., Wang, Y., Yang, F., Li, W., & Guo, X. (2026) · BMC Cancer · doi:10.1186/s12885-026-16479-0
“Doublecortin like kinase 3 (DCLK3) is a serine/threonine protein kinase that plays critical roles in various physiological processes [6].”
- Authors
- Galvan, L., Francelle, L., Gaillard, M.-C., de Longprez, L., Carrillo-de Sauvage, M.-A., Liot, G., Cambon, K., Stimmer, L., Luccantoni, S., Flament, J., Valette, J., de Chaldée, M., Auregan, G., Guillermier, M., Joséphine, C., Petit, F., Jan, C., Jarrige, M., Dufour, N., Bonvento, G., Humbert, S., Saudou, F., Hantraye, P., Merienne, K., Bemelmans, A.-P., Perrier, A. L., Déglon, N., & Brouillet, E.
- Affiliations
- Centre National de la Recherche Scientifique (FR)
- CEA, DRF, Institut François Jacob, Molecular Imaging Research Center (MIRCen), F-92265 Fontenay-aux-Roses, France
- Inserm (FR)
- Institute for Integrative Biology of the Cell (I2BC), CEA, CNRS, Univ. Paris-Sud, Univ. Paris-Saclay, 91191 Gif-sur-Yvette Cedex, France
- CNRS/Strasbourg University UMR 7364, Laboratory of Adaptive and Cognitive Neuroscience (LNCA), Strasbourg F-67000, France
- Centre Hospitalier Universitaire Vaudois (CH)
- Corresponding author
- Brouillet, Emmanuel
- ORCID
- Venue
- Brain
- Publisher
- Oxford University Press (OUP)
- Published
- 2018-03-09
- Volume
- 141
- Issue
- 5
- Pages
- 1434-1454
- ISSN
- 0006-8950 (ISSN-L)
- 1460-2156
- PMC
- PMC5917821
- OpenAlex
- W2790952913
- Cited by
- 47
- References
- 58
- Citations by year
- 2026: 2 · 2025: 10 · 2023: 12 · 2022: 6 · 2021: 4 · 2020: 7 · 2019: 4 · 2018: 2
- FWCI
- 1.94
- Type
- journal article
- Language
- en
- Open access
- hybrid
- doi.org
- Licence
- Locations
- Brain (publishedVersion, cc-by-nc)
- Europe PMC (PubMed Central) (publishedVersion, cc-by-nc)
- PubMed Central (publishedVersion, cc-by-nc)
- PubMed (publishedVersion)
- SERVAL (Université de Lausanne) (publishedVersion, cc-by-nc)
- HAL (submittedVersion, other-oa)
- IRIS (submittedVersion, cc-by-nc)
- HAL (submittedVersion)
- Funders
- Agence Nationale de la Recherche (ANR-17-CE12-0027, ANR-11-INBS, ANR-11-INBS-0011)
- Topics
- Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Genetic Neurodegenerative Diseases
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Genetics and Neurodevelopmental Disorders
- Health Sciences › Medicine › Neurology › Amyotrophic Lateral Sclerosis Research
- Keywords
- Huntington's disease, mutant huntingtin, neuroprotection, striatal neurons, kinase activity, transcriptional regulation, chromatin remodeling, SAGA complex, histone acetylation, zinc finger proteins, neurodegeneration, motor symptoms
- MeSH terms
- Huntingtin Protein, Doublecortin-Like Kinases, Animals, Cells, Cultured, Corpus Striatum, Electron Transport Complex IV, Disease Models, Animal, Huntington Disease, Macaca fascicularis, Male, Mice, Inbred C57BL, Mice, Transgenic, Motor Activity, Mutation, Neurons, Phosphopyruvate Hydratase, Transcription Factors, Trans-Activators, Down-Regulation, Protein Serine-Threonine Kinases, Hand Strength, RNA, Small Interfering, Mice
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 ›
Are you an author, or do you see a problem with this page? Request a review
