Time-dependent Conditional Knockout Rat Models (Inducible)
A time-dependent conditional Knockout rat defines an inducible animal model in which a gene of interest is "floxed" thus temporally controllable at a given time-point in embryonic, post-natal or adult animals.
After an additional breeding step with a Cre-inducible deleter rat line, the conditional Knockout is temporally triggered by external inducer-agents, most often small molecules such as tamoxifen or tetracycline.
Typical applications for time-dependent conditional Knockout rat models
For academic research:
For bio-pharmaceutical research & development:
Strengths and limitations of time-dependent conditional Knockout rat models
- Very flexible: easy switch to study time-dependent KOs in different tissues
- High physiological relevancy of the scientific data obtained from the model
- Very low availability of different Cre-inducible deleter rat lines may require the creation of a new Cre-inducible rat with an adequate genetic background
→ New Cre-inducible rat lines can be produced by genOway in parallel to the conditional rat model
- Expression levels depend on the dose of the agent administered
- Differential penetration of trigger compound into tissue
- Adding the loxP sites risks modification or disruption of splicing regulation (ESS ESE); possible impact on overlapping and neighboring genes
→ Need careful analysis of the placement of loxP sites
- Tetracycline-inducible systems can leak
→ Temporal control can be achieved by using a fusion between Cre and a mutated form of the ligand-binding domain of the estrogen receptor, which only binds tamoxifen (ERt and ERt2). This inactive Cre-ERt2 fusion is activated upon tamoxifen (or 4-hydroxytamoxifen) administration.
Selection of genOway clients' publications on rat models
Comasco E, Schijven D, de Maeyer H, Vrettou M, Nylander I, Sundström-Poromaa I, Olivier JD.
Constitutive serotonin transporter reduction resembles maternal separation with regard to stress-related gene expression.
ACS Chem Neurosci. 2019
Visceral hypersensitivity & IBS
El-Ayache N, Galligan JJ.
5-HT3 receptor signaling in serotonin transporter knockout rats: a female sex specific animal model of visceral hypersensitivity.
Am J Physiol Gastrointest Liver Physiol. 2018
Micheli L, Di Cesare Mannelli L, Guerrini R, Trapella C, Zanardelli M, Ciccocioppo R, Rizzi A, Ghelardini C, Calò G.
Acute and subchronic antinociceptive effects of nociceptin/orphanin FQ receptor agonists infused by intrathecal route in rats.
Eur J Pharmacol. 2015
Galligan JJ, Patel BA, Schneider SP, Wang H, Zhao H, Novotny M, Bian X, Kabeer R, Fried D, Swain GM.
Visceral hypersensitivity in female but not in male serotonin transporter knockout rats.
Neurogastroenterol Motil. 2013
Lizarraga LE, Phan AV, Cholanians AB, Herndon JM, Lau SS, Monks TJ
Serotonin reuptake transporter deficiency modulates the acute thermoregulatory and locomotor activity response to 3,4-(±)-methylenedioxymethamphetamine, and attenuates depletions in serotonin levels in SERT-KO rats.
Toxicol Sci. 2014
Saheb-Al-Zamani M, Yan Y, Farber SJ, Hunter DA, Newton P, Wood MD, Stewart SA, Johnson PJ, Mackinnon SE.
Limited regeneration in long acellular nerve allografts is associated with increased Schwann cell senescence.
Exp Neurol. 2013
Sun HH, Saheb-Al-Zamani M, Yan Y, Hunter DA, Mackinnon SE, Johnson PJ.
Geldanamycin accelerated peripheral nerve regeneration in comparison to FK-506 in vivo.
Moore AM, Borschel GH, Santosa KA, Flagg ER, Tong AY, Kasukurthi R, Newton P, Yan Y, Hunter DA, Johnson PJ, Mackinnon SE.
A transgenic rat expressing green fluorescent protein (GFP) in peripheral nerves provides a new hindlimb model for the study of nerve injury and regeneration.
J Neurosci Methods. 2012
Magill CK, Moore AM, Borschel GH, Mackinnon SE.
A new model for facial nerve research: the novel transgenic Thy1-GFP rat.
Arch Facial Plast Surg. 2010
Ménoret S, Ouisse LH, Tesson L, Delbos F, Garnier D, Remy S, Usal C, Concordet JP, Giovannangeli C, Chenouard V, Brusselle L, Merieau E, Nerrière-Daguin V, Duteille F, Bellier-Waast F, Fraichard A, Nguyen TH, Anegon I.
Generation of immunodeficient rats with Rag1 and Il2rg gene deletions and human tissue grafting models.
Ménoret S, Fontanière S, Jantz D, Tesson L, Thinard R, Rémy S, Usal C, Ouisse LH, Fraichard A, Anegon I.
Generation of Rag1-knockout immunodeficient rats and mice using engineered meganucleases.
FASEB J. 2013
Pavlovic D, Hall AR, Kennington EJ, Aughton K, Boguslavskyii A, Fuller W, Despa S, Bers DM, Shattock MJ.
Nitric oxide regulates cardiac intracellular Na+ and Ca2+ by modulating Na/K ATPase via PKCε and phospholemman-dependent mechanism.
J Mol Cell Cardiol. 2013
Franquesa M, Herrero E, Torras J, Ripoll E, Flaquer M, Gomà M, Lloberas N, Anegon I, Cruzado JM, Grinyó JM, Herrero-Fresneda I.
Mesenchymal Stem Cell Therapy Prevents Interstitial Fibrosis and Tubular Atrophy in a Rat Kidney Allograft Model.
Stem Cells Dev. 2012
Lelan F, Boyer C, Thinard R, Rémy S, Usal C, Tesson L, Anegon I, Neveu I, Damier P, Naveilhan P, Lescaudron L.
Effects of Human Alpha-Synuclein A53T-A30P Mutations on SVZ and Local Olfactory Bulb Cell Proliferation in a Transgenic Rat Model of Parkinson Disease.
Parkinsons Dis. 2011
Patrick Davis R, Linder AE, Watts SW.
Lack of the serotonin transporter (SERT) reduces the ability of 5-hydroxytryptamine to lower blood pressure.
Naunyn Schmiedebergs Arch Pharmacol. 2011
Linder AE, Davis RP, Burnett R, Watts SW.
Comparison of the function of the serotonin transporter in the vasculature of male and female rats.
Clin Exp Pharmacol Physiol. 2011
Ren W, Watts SW, Fanburg BL.
Serotonin transporter interacts with the PDGFβ receptor in PDGF-BB-induced signaling and mitogenesis in pulmonary artery smooth muscle cells.
Am J Physiol Lung Cell Mol Physiol. 2011
Johnson PL, Molosh AI, Federici LM, Bernabe C, Haggerty D, Fitz SD, Nalivaiko E, Truitt W, Shekhar A.
Assessment of fear and anxiety associated behaviors, physiology and neural circuits in rats with reduced serotonin transporter (SERT) levels.
Transl Psychiatry. 2019
Rizzi A, Molinari S, Marti M, Marzola G, Calo' G.
Nociceptin/orphanin FQ receptor knockout rats: in vitro and in vivo studies.
Rutten K, De Vry J, Bruckmann W, Tzschentke TM.
Pharmacological blockade or genetic knockout of the NOP receptor potentiates the rewarding effect of morphine in rats.
Drug Alcohol Depend. 2011
Linder AE, Beggs KM, Burnett RJ, Watts SW.
Body distribution of infused serotonin in rats.
Clin Exp Pharmacol Physiol. 2009