Constitutive Knockout Mouse Models (Conventional)

 



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A constitutive Knockout mouse, also referred to as a conventional or whole-body Knockout (KO), defines a mouse model in which the target gene is permanently inactivated in the whole animal, in every cell of the organism.

This gene inactivation is achieved at all stages of development, from the one-cell embryo stage through adulthood.

Infographic: Conventional Knockout mouse model

Typical applications for constitutive KO mouse models


For academic research:
  • Determine main functions of the gene and/or protein
  • Study human pathologies caused by gene inactivation or deficiency
  • Induce a phenotype to create a disease model or in vivo research tool
For bio-pharmaceutical research & development:
  • Validate target gene
  • Study specificity and/or off-target activities of drug candidate
  • Develop new antibodies on the target protein
  • Safety and toxicology studies

Strengths and limitations of constitutive KO mouse models

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  • Total absence of protein including all isoforms, or total absence of specific isoforms
  • Fast solution for preliminary in vivo studies
  • Feasible in all genetic backgrounds
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  • Causes embryonic lethality in about 15% of all cases
  • May modify the animal physiology, adaptation and compensation mechanisms, resulting in false results
  • Global phenotype is the combination of different constitutions in different tissues that may lead to non-conclusive studies

→  These limitations can be bypassed by applying conditions such as time- or tissue-specificity



Case studies and publications on our constitutive Knockout mouse models

Case studies

Model for idiopathic Parkinson’s disease (idPD)

Zhou Q, Yen A, Rymarczyk G, Asai H, Trengrove C, Aziz N, Kirber MT, Mostoslavsky G, Ikezu T, Wolozin B, Bolotina VM.
Impairment of PARK14-dependent Ca(2+) signalling is a novel determinant of Parkinson's disease.
Nat Commun. 2016.

Cells from idPD patients reveal a significant deficiency in store-operated PLA2G6-dependent Ca2+ signaling. The Pla2g6 gene (PARK14 disease locus) is poorly understood.

Model: Mice that constitutively lack the Pla2g6 gene mimicking the pathology observed in idPD patients.

Aim: Explore the origins of human age-dependent PD from the new perspective of PARK14 and the store-operated Ca2+ signaling, opening new opportunities for finding a cure for idPD.

Results: The molecular impairment of PLA2G6-dependent Ca2+ signaling triggers a sequence of pathological events of autophagic dysfunction, progressive loss of dopaminergic (DA) neurons in substantia nigra pars compacta and age-dependent L-DOPA-sensitive motor dysfunction.

Figure 1. PLA2G6 KO mice mimic store-operated Ca2+ entry (SOCE) deficiency in idPD patients.

Figure 1a - PLA2G6 KO mice A) Live primary skin fibroblasts from idPD and control donors were pretreated with thapsigargin (TG) to induce Ca2+ influx prior to Ca2+ addition. On average, there was more than 40% reduction in TG-induced Ca2+ influx in idPD patients compared with the control group.
Figure 1b - PLA2G6 KO mice Figure 1c - PLA2G6 KO mice
B-C) MEFs (B) and iPSC-derived DA neurons (C) from WT and PLA2G6 KO mice were pretreated with TG prior to CA2+ addition. Impairment of TG-induced Ca2+ influx in the PLA2G6 KO mice mimics the defect found in fibroblasts of idPD patients.

 

Figure 2. PLA2G6 KO mice develop age-dependent PD-like phenotype.

Figure 2 - PLA2G6 KO mice

 

Progressive motor dysfunction in aging KO, but not in WT mice developed at an age range that aligns with that typical of idPD in humans. Human age equivalent is shown below.

Publications

2018

Gago-Fuentes R, Xing M, Sæterstad S, Sarno A, Dewan A, Beck C, Bradamante S, Bjørås M, Oksenych V.
Normal development of mice lacking PAXX, the paralogue of XRCC4 and XLF.
FEBS Open Bio. 2018 Feb 4.


2016

Joffre J, Potteaux S, Zeboudj L, Loyer X, Boufenzer A, Laurans L, Esposito B, Vandestienne M, de Jager SC, Hénique C, Zlatanova I, Taleb S, Bruneval P, Tedgui A, Mallat Z, Gibot S, Ait-Oufella H.
Genetic and Pharmacological Inhibition of TREM-1 Limits the Development of Experimental Atherosclerosis.
J Am Coll Cardiol. 2016 Dec 27.

Grauel MK, Maglione M, Reddy-Alla S, Willmes CG, Brockmann MM, Trimbuch T, Rosenmund T, Pangalos M, Vardar G, Stumpf A, Walter AM, Rost BR, Eickholt BJ, Haucke V, Schmitz D, Sigrist SJ, Rosenmund C.
RIM-binding protein 2 regulates release probability by fine-tuning calcium channel localization at murine hippocampal synapses.
Proc Natl Acad Sci U S A. 2016 Sep 26.

Komnenov D, Solarewicz JZ, Afzal F, Nantwi KD, Kuhn DM, Mateika JH.
Intermittent hypoxia promotes recovery of respiratory motor function in spinal cord-injured mice depleted of serotonin in the central nervous system.
J Appl Physiol (1985). 2016 Aug.

Vingtdeux V, Chang EH, Frattini SA, Zhao H, Chandakkar P, Adrien L, Strohl JJ, Gibson EL, Ohmoto M, Matsumoto I, Huerta PT, Marambaud P.
CALHM1 deficiency impairs cerebral neuron activity and memory flexibility in mice.
Sci Rep. 2016 Apr 12.

Imeri F, Schwalm S, Lyck R, Zivkovic A, Stark H, Engelhardt B, Pfeilschifter J, Huwiler A.
Sphingosine kinase 2 deficient mice exhibit reduced experimental autoimmune encephalomyelitis: Resistance to FTY720 but not ST-968 treatments.
Neuropharmacology. 2016 Jan 23.

Zhou Q, Yen A, Rymarczyk G, Asai H, Trengrove C, Aziz N, Kirber MT, Mostoslavsky G, Ikezu T, Wolozin B, Bolotina VM.
Impairment of PARK14-dependent Ca(2+) signalling is a novel determinant of Parkinson's disease.
Nat Commun. 2016 Jan 12.


2015

Onal M, St John HC, Danielson AL, Markert JW, Riley EM, Pike JW.
Unique Distal Enhancers Linked to the Mouse Tnfsf11 Gene Direct Tissue-Specific and Inflammation-induced Expression of RANKL.
Endocrinology. 2015 Dec 8.

Onal M, St John HC, Danielson AL, Pike JW.
Deletion of the Distal Tnfsf11 RL-D2 Enhancer that Contributes to PTH-Mediated RANKL Expression in Osteoblast Lineage Cells Results in a High Bone Mass Phenotype in Mice.
J Bone Miner Res. 2015 Aug 31.

Hellekant G, Schmolling J, Marambaud P, Rose-Hellekant TA.
CALHM1 Deletion in Mice Affects Glossopharyngeal Taste Responses, Food Intake, Body Weight, and Life Span.
Chem Senses. 2015 Apr 8.

Wang SK, Hu Y, Yang J, Smith CE, Nunez SM, Richardson AS, Pal S, Samann AC, Hu JC, Simmer JP.
Critical roles for WDR72 in calcium transport and matrix protein removal during enamel maturation.
Mol Genet Genomic Med. 2015 Mar 29.

Angoa-Pérez M, Herrera-Mundo N, Kane MJ, Sykes CE, Anneken JH, Francescutti DM, Kuhn DM.
Brain serotonin signaling does not determine sexual preference in male mice.
PLoS One. 2015 Feb 23.

Alfarano C, Foussal C, Lairez O, Calise D, Attané C, Anesia R, Daviaud D, Wanecq E, Parini A, Valet P, Kunduzova O.
Transition from metabolic adaptation to maladaptation of the heart in obesity: role of apelin.
Int J Obes (Lond). 2015 Feb.

Solarewicz JZ, Angoa-Perez M, Kuhn DM, Mateika JH.
The sleep-wake cycle and motor activity, but not temperature, are disrupted over the light-dark cycle in mice genetically depleted of serotonin.
Am J Physiol Regul Integr Comp Physiol. 2015 Jan 1.


2014

Pagliarani S, Lucchiari S, Ulzi G, Violano R, Ripolone M, Bordoni A, Nizzardo M, Gatti S, Corti S, Moggio M, Bresolin N, Comi GP
Glycogen storage disease type III: A novel Agl knockout mouse model.
Biochim Biophys Acta. 2014 Nov.

Angoa-Pérez M, Kane MJ, Briggs DI, Herrera-Mundo N, Sykes CE, Francescutti DM, Kuhn DM.
Mice genetically depleted of brain serotonin do not display a depression-like behavioral phenotype.
ACS Chem Neurosci. 2014 Oct 15.

Angoa-Pérez M, Kane MJ, Sykes CE, Perrine SA, Church MW, Kuhn DM.
Brain serotonin determines maternal behavior and offspring survival.
Genes Brain Behav. 2014 Sep.

Sun Y, Caplazi P, Zhang J, Mazloom A, Kummerfeld S, Quinones G, Senger K, Lesch J, Peng I, Sebrell A, Luk W, Lu Y, Lin Z, Barck K, Young J, Del Rio M, Lehar S9, Asghari V8, Lin W1, Mariathasan S9, DeVoss J1, Misaghi S10, Balazs M1, Sai T5, Haley B, Hass PE, Xu M, Ouyang W, Martin F, Lee WP, Zarrin AA
PILRα negatively regulates mouse inflammatory arthritis.
J Immunol. 2014 Jul 15.

Tordoff MG, Ellis HT, Aleman TR, Downing A, Marambaud P, Foskett JK, Dana RM, McCaughey SA
Salty Taste Deficits in CALHM1 Knock-out Mice.
Chem Senses. 2014 Jul.

Polato F, Rusconi P, Zangrossi S, Morelli F, Boeri M, Musi A, Marchini S, Castiglioni V, Scanziani E, Torri V, Broggini M
DRAGO (KIAA0247), a New DNA Damage-Responsive, p53-Inducible Gene That Cooperates With p53 as Oncosupprossor.
J Natl Cancer Inst. 2014 Apr.

Hickner S, Hussain N, Angoa-Perez M, Francescutti DM, Kuhn DM, Mateika JH.
Ventilatory long-term facilitation is evident after initial and repeated exposure to intermittent hypoxia in mice genetically depleted of brain serotonin.
J Appl Physiol (1985). 2014 Feb 1.


2013

Angoa-Pérez M, Kane MJ, Briggs DI, Francescutti DM, Kuhn DM.
Marble burying and nestlet shredding as tests of repetitive, compulsive-like behaviors in mice.
J Vis Exp. 2013 Dec 24.

Lengacher S, Nehiri-Sitayeb T, Steiner N, Carneiro L, Favrod C, Preitner F, Thorens B, Stehle JC, Dix L, Pralong F, Magistretti PJ, Pellerin L.
Resistance to diet-induced obesity and associated metabolic perturbations in haploinsufficient monocarboxylate transporter 1 mice.
PLoS One. 2013 Dec 18.

Huntwork-Rodriguez S, Wang B, Watkins T, Ghosh AS, Pozniak CD, Bustos D, Newton K, Kirkpatrick DS, Lewcock JW.
JNK-mediated phosphorylation of DLK suppresses its ubiquitination to promote neuronal apoptosis.
J Cell Biol. 2013 Sep 2.

Prieur X, Dollet L, Takahashi M, Nemani M, Pillot B, Le May C, Mounier C, Takigawa-Imamura H, Zelenika D, Matsuda F, Fève B, Capeau J, Lathrop M, Costet P, Cariou B, Magré J.
Thiazolidinediones partially reverse the metabolic disturbances observed in Bscl2/seipin-deficient mice.
Diabetologia. 2013 May 17.

Taruno A, Vingtdeux V, Ohmoto M, Ma Z, Dvoryanchikov G, Li A, Adrien L, Zhao H, Leung S, Abernethy M, Koppel J, Davies P, Civan MM, Chaudhari N, Matsumoto I, Hellekant G, Tordoff MG, Marambaud P, Foskett JK.
CALHM1 ion channel mediates purinergic neurotransmission of sweet, bitter and umami tastes.
Nature. 2013 Mar 6.

Dreses-Werringloer U, Vingtdeux V, Zhao H, Chandakkar P, Davies P, Marambaud P.
CALHM1 controls Ca2+-dependent MEK/ERK/RSK/MSK signaling in neurons.
J Cell Sci. 2013 Jan 23.


2012

Kane MJ, Angoa-Peréz M, Briggs DI, Sykes CE, Francescutti DM, Rosenberg DR, Kuhn DM.
Mice genetically depleted of brain serotonin display social impairments, communication deficits and repetitive behaviors: possible relevance to autism.
PLoS One. 2012 Nov 6.

Caparrós-Martín JA, Valencia M, Reytor E, Pacheco M, Fernandez M, Perez-Aytes A, Gean E, Lapunzina P, Peters H, Goodship JA, Ruiz-Perez VL.
The ciliary Evc/Evc2 complex interacts with Smo and controls Hedgehog pathway activity in chondrocytes by regulating Sufu/Gli3 dissociation and Gli3 trafficking in primary cilia.
Hum Mol Genet. 2012 Nov 1.

Bickert T, Marshall RP, Zhang Z, Ludewig P, Binder M, Klinke A, Rottbauer W, Amling M, Wagener C, Ito WD, Horst AK.
Acceleration of collateral development by carcinoembryonic antigen-related cell adhesion molecule 1 expression on CD11b/⁺Gr-1⁺ myeloid cells--brief report.
Arterioscler Thromb Vasc Biol. 2012 Nov.

Kolb AF, Sorrell D, Lassnig C, Lillico S, Carlisle A, Neil C, Robinson C, Müller M, Whitelaw CB.
Mammary gland development is delayed in mice deficient for aminopeptidase N.
Transgenic Res. 2012 Sep 15.

Martin J, Maurhofer O, Bellance N, Benard G, Graber F, Hahn D, Galinier A, Hora C, Gupta A, Ferrand G, Hoppeler H, Rossignol R, Dufour JF, St-Pierre MV.
Disruption of the histidine triad nucleotide-binding hint2 gene in mice affects glycemic control and mitochondrial function.
Hepatology. 2012 Sep 7.

Ma Z, Siebert AP, Cheung KH, Lee RJ, Johnson B, Cohen AS, Vingtdeux V, Marambaud P, Foskett JK.
Calcium homeostasis modulator 1 (CALHM1) is the pore-forming subunit of an ion channel that mediates extracellular Ca2+ regulation of neuronal excitability.
Proc Natl Acad Sci U S A. 2012 Jul 10.

Daude N, Wohlgemuth S, Brown R, Pitstick R, Gapeshina H, Yang J, Carlson GA, Westaway D.
Knockout of the prion protein (PrP)-like Sprn gene does not produce embryonic lethality in combination with PrP(C)-deficiency.
Proc Natl Acad Sci U S A. 2012 Jun 5.

Angoa-Pérez M, Kane MJ, Briggs DI, Sykes CE, Shah MM, Francescutti DM, Rosenberg DR, Thomas DM, Kuhn DM.
Genetic depletion of brain 5HT reveals a common molecular pathway mediating compulsivity and impulsivity.
J Neurochem. 2012 Jun.


2011

Di Cara B, Maggio R, Aloisi G, Rivet JM, Lundius EG, Yoshitake T, Svenningsson P, Brocco M, Gobert A, De Groote L, Cistarelli L, Veiga S, De Montrion C, Rodriguez M, Galizzi JP, Lockhart BP, Cogé F, Boutin JA, Vayer P, Verdouw PM, Groenink L, Millan MJ.
Genetic deletion of trace amine 1 receptors reveals their role in auto-inhibiting the actions of ecstasy (MDMA).
J Neurosci. 2011 Nov 23.

Sejersted Y, Hildrestrand GA, Kunke D, Rolseth V, Krokeide SZ, Neurauter CG, Suganthan R, Atneosen-Åsegg M, Fleming AM, Saugstad OD, Burrows CJ, Luna L, Bjørås M.
Endonuclease VIII-like 3 (Neil3) DNA glycosylase promotes neurogenesis induced by hypoxia-ischemia.
Proc Natl Acad Sci U S A. 2011 Nov 15.

Andreas F. Kolb, Reinhard C. Huber, Simon G. Lillico, Ailsa Carlisle, Claire J. Robinson, Claire Neil, Linda Petrie, Dorte B. Sorensen, I. Anna S. Olsson, C. Bruce A. Whitelaw.
Milk Lacking α-Casein Leads to Permanent Reduction in Body Size in Mice.
PlosOne. 2011 July 18.

Lawan A, Al-Harthi S, Cadalbert L, McCluskey AG, Shweash M, Grassia G, Grant A, Boyd M, Currie S, Plevin R.
Deletion of the Dual Specific Phosphatase-4 (DUSP-4) Gene Reveals an Essential Non-redundant Role for MAP Kinase Phosphatase-2 (MKP-2) in Proliferation and Cell Survival.
J Biol Chem. 2011 Apr 15.

van den Born E, Vågbø CB, Songe-Møller L, Leihne V, Lien GF, Leszczynska G, Malkiewicz A, Krokan HE, Kirpekar F, Klungland A, Falnes PØ.
ALKBH8-mediated formation of a novel diastereomeric pair of wobble nucleosides in mammalian tRNA.
Nat Commun. 2011 Feb 1.


2010

Abdul-Sater AA, Saïd-Sadier N, Lam VM, Singh B, Pettengill MA, Soares F, Tattoli I, Lipinski S, Girardin SE, Rosenstiel P, Ojcius DM.
Enhancement of reactive oxygen species production and chlamydial infection by the mitochondrial Nod-like family member NLRX1.
J Biol Chem. 2010 Dec 31.

Al-Mutairi MS, Cadalbert LC, McGachy HA, Shweash M, Schroeder J, Kurnik M, Sloss CM, Bryant CE, Alexander J, Plevin R.
MAP kinase phosphatase-2 plays a critical role in response to infection by Leishmania mexicana.
PLoS Pathog. 2010 Nov 11.

Thomas DM, Angoa Pérez M, Francescutti-Verbeem DM, Shah MM, Kuhn DM.
The role of endogenous serotonin in methamphetamine-induced neurotoxicity to dopamine nerve endings of the striatum.
J Neurochem. 2010 Nov.

Ledonne A, Federici M, Giustizieri M, Pessia M, Imbrici P, Millan MJ, Bernardi G, Mercuri NB.
Trace amines depress D(2)-autoreceptor-mediated responses on midbrain dopaminergic cells.
Br J Pharmacol. 2010 Jul.

Songe-Møller L, van den Born E, Leihne V, Vågbø CB, Kristoffersen T, Krokan HE, Kirpekar F, Falnes PØ, Klungland A.
Mammalian ALKBH8 possesses tRNA methyltransferase activity required for the biogenesis of multiple wobble uridine modifications implicated in translational decoding.
Mol Cell Biol. 2010 Apr;30(7):1814-27.


2002-2009

Steinmetz OM, Turner JE, Paust HJ, Lindner M, Peters A, Heiss K, Velden J, Hopfer H, Fehr S, Krieger T, Meyer-Schwesinger C, Meyer TN, Helmchen U, Mittrücker HW, Stahl RA, Panzer U.
CXCR3 mediates renal Th1 and Th17 immune response in murine lupus nephritis.
J Immunol. 2009 Oct 1.

Johswich K, Martin M, Bleich A, Kracht M, Dittrich-Breiholz O, Gessner JE, Suerbaum S, Wende E, Rheinheimer C, Klos A.
Role of the C5a receptor (C5aR) in acute and chronic dextran sulfate-induced models of inflammatory bowel disease.
Inflamm Bowel Dis. 2009 Aug 27.

Pushparaj PN, Manikandan J, Tay HK, H'ng SC, Kumar SD, Pfeilschifter J, Huwiler A, Melendez AJ.
Sphingosine kinase 1 is pivotal for Fc epsilon RI-mediated mast cell signaling and functional responses in vitro and in vivo.
J Immunol. 2009 Jul 1.

Dobbertin A, Hrabovska A, Dembele K, Camp S, Taylor P, Krejci E, Bernard V.
Targeting of acetylcholinesterase in neurons in vivo: a dual processing function for the proline-rich membrane anchor subunit and the attachment domain on the catalytic subunit.
J Neurosci. 2009 Apr 8.

Hofmann LP, Ren S, Schwalm S, Pfeilschifter J, Huwiler A.
Sphingosine kinase 1 and 2 regulate the capacity of mesangial cells to resist apoptotic stimuli in an opposing manner.
Biol Chem. 2008 Nov.

Rodríguez C, López P, Pozo M, Duce AM, López-Pelaéz M, Fernández M, Alemany S.
COX2 expression and Erk1/Erk2 activity mediate Cot-induced cell migration.
Cell Signal. 2008 Sep.

Rahuel C, Filipe A, Ritie L, El Nemer W, Patey-Mariaud N, Eladari D, Cartron JP, Simon-Assmann P, Le Van Kim C, Colin Y.
Genetic inactivation of the laminin alpha5 chain receptor Lu/BCAM leads to kidney and intestinal abnormalities in the mouse.
Am J Physiol Renal Physiol. 2008 Feb.

Panzer U, Steinmetz OM, Paust HJ, Meyer-Schwesinger C, Peters A, Turner JE, Zahner G, Heymann F, Kurts C, Hopfer H, Helmchen U, Haag F, Schneider A, Stahl RA.
Chemokine receptor CXCR3 mediates T cell recruitment and tissue injury in nephrotoxic nephritis in mice.
J Am Soc Nephrol. 2007 Jul.

Klawitter S, Hofmann LP, Pfeilschifter J, Huwiler A.
Extracellular nucleotides induce migration of renal mesangial cells by upregulating sphingosine kinase-1 expression and activity.
Br J Pharmacol. 2007 Feb.

Goossens D, Bony V, Gane P, Colin Y, Cartron JP.
Generation of mice with inactivated Rh or Rhag genes.
Transfus Clin Biol. 2006 Apr.

Chambrey R, Goossens D, Bourgeois S, Picard N, Bloch-Faure M, Leviel F, Geoffroy V, Cambillau M, Colin Y, Paillard M, Houillier P, Cartron JP, Eladari D
Genetic ablation of Rhbg in the mouse does not impair renal ammonium excretion.
Am J Physiol Renal Physiol. 2005 Dec.

Ross AJ, May-Simera H, Eichers ER, Kai M, Hill J, Jagger DJ, Leitch CC, Chapple JP, Munro PM, Fisher S, Tan PL, Phillips HM, Leroux MR, Henderson DJ, Murdoch JN, Copp AJ, Eliot MM, Lupski JR, Kemp DT, Dollfus H, Tada M, Katsanis N, Forge A, Beales PL.
Disruption of Bardet-Biedl syndrome ciliary proteins perturbs planar cell polarity in vertebrates.
Nat Genet. 2005 Oct.

Mailliet F, Ferry G, Vella F, Thiam K, Delagrange P, Boutin JA.
Organs from mice deleted for NRH:quinone oxidoreductase 2 are deprived of the melatonin binding site MT3.
FEBS Lett. 2004 Dec 3.

Chevillard G, Clemencet MC, Latruffe N, Nicolas-Frances V.
Targeted disruption of the peroxisomal thiolase B gene in mouse: a new model to study disorders related to peroxisomal lipid metabolism.
Biochimie. 2004 Nov.

Roselli S, Heidet L, Sich M, Henger A, Kretzler M, Gubler MC, Antignac C.
Early glomerular filtration defect and severe renal disease in podocin-deficient mice.
Mol Cell Biol. 2004 Jan.

Merlo GR, Paleari L, Mantero S, Genova F, Beverdam A, Palmisano GL, Barbieri O, Levi G.
Mouse model of split hand/foot malformation type I.
Genesis. 2002 Jun.

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