Time-dependent Conditional Knockout Rat Models (Inducible)

 



Get supplemental information, a quote, and estimated timeframe for generating your inducible Knockout rat line.

 

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.

Infographic: Time-dependent Knockout rat model

Typical applications for time-dependent conditional Knockout rat models


For academic research:
  • Comparative study of gene function (onset vs. offset)
  • Mimic a pathology with late onset
  • Studying embryonic lethal conditions
For bio-pharmaceutical research & development:
  • Target validation studies
  • Off-target effects studies
  • Mimicking 100% antagonism
  • Compensatory phenotype rescue (compounds testing)

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

Pain

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

Thermoregulation

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

Neuronal regeneration

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.
Neuroscience. 2012

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

Immunodeficiency

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.
Transplantation. 2018

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

Cardiac function

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

Transplantation

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

Parkinson disease

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

Hypertension

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

Depression

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

Respiration

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

Anxiety

Rizzi A, Molinari S, Marti M, Marzola G, Calo' G.
Nociceptin/orphanin FQ receptor knockout rats: in vitro and in vivo studies.
Neuropharmacology. 2011

Drug abuse

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

Physiology

Linder AE, Beggs KM, Burnett RJ, Watts SW.
Body distribution of infused serotonin in rats.
Clin Exp Pharmacol Physiol. 2009

 

Follow these links if you are looking for a tissue-specific Knockout rat, or another customized rat model.