Inducible-tissue specific Cre-loxP system for in vivo and in vitro study


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Product list: Cre/loxP tools in AAV vector(AAV-Cre), adenoviral vector(Ad-Cre) and lentiviral vector(Lv-Cre)


Cre-loxP system is widely used in the field of biosciences, especially in the generation of genetically engineered mice (knockout or overexpression), enabling researchers to study the function of gene of interest (GOI). To date, numerous systems, derived from the basic Cre-loxP system, have been developed to precisely control gene expression at desired time or cells. Here, we briefly introduce Cre-loxP system, and give a summary about its applications, especially viral vectors-mediated Cre expression (such as AAV-Cre or Ad-Cre) for in vitro or in vivo studies.

Inducible-tissue specific Cre-loxP system for in vivo and in vitro study

a) Tissue-specific promoter driven Cre-loxP system for conditional knock-out (KO)

To achieve the conditional knock-out (KO) of gene of interest (GOI) in specific tissue or organ, cell-specific promoter/enhancer driven Cre lines are used to breed with GOI-loxP lines. Their offspring will get both cell-specific driven Cre and floxed DNA (GOI), resulting in tissue-specific GOI excision (Fig. 3). A great number of cell-specific promoters or enhancers have been developed, such as Lyz2 driven Cre specific in macrophage, and CD45 driven Cre specific in hematopoietic tissues. Some examples are listed in the following Table 1.

Figure 3. Generation schematics for conditional knock-out (KO) using tissue-specific Cre/loxP tool. In principle, one mouse with tissue (X)-specific driven Cre gene breeds with another mouse with floxed GOI, producing offspring carrying floxed GOI Y and Cre recombinase in tissue X. Thus, GOI Y would be excised by Cre in tissue X [7]. GOI, gene of interest.
Table 1. Examples of tissue-specific promoter driven Cre-loxP system
Tissue/organ cell Promoter/enhancer Reference
Cerebrum Neuronal and glia cell precursors Aldh1l1 [12]
GABAergic interneuronsDlx1[14]
GABAergic neuronsDlx5/6[15-17] 
AstrocyteGFAP[19, 20]
CA3 pyramidal cellsGrik4[21]
Arcuate nucleusLepr[22]
Neuronal and glia cell precursorsNes[23]
DRG neuronsnNOS[18]
Retinal Müller glial cellsPdgfrα[24]
Myelinating cellsPLP1[25]
DRG neuronsPv (Pvalb)[18]
GABAergic neuronsSlc17a6[26]
GABAergic neuronsSst, Vip[17]
CerebellumCerebellar Purkinje cellsPcp2[27]
Brain stemDopamine and serotonin neuronsSlc6a3 (DAT)[28]
Serotonin neuronsePet (Fev)[29]
Vagal sensory neuronsNpy2r[30]
Spinal cordMechanosensory dorsal hornCdh3, Htr6[31]
SkinBasal layer of the epidermisKrt5[32]
Epidermis keratinocytesKrt10[33]
Epidermal progenitors Krt18[34]
Immune systemMacrophageLyz2[35]
Dendritic cellsCD11c (Itgax)[36]
Mast cellsCMA1[37]
T cellsCD2[38]
B cellsCD19[44, 45]
Hematopoietic cellsCD15[46]
MusculoskeletalOsteochondro progenitorsTwist2 (Dermol)[47, 48]
MuscleACTA1 (HSA)[54]
Digestive systemStomachATP4b[55]
LiverAlb[58, 59]
Ins1 (MIP)[61]
Ins2 (RIP)[62]
Urogenital systemBladderUpk2[64]

b) Inducible Cre-loxP system

One inducible system is tamoxifen-inducible Cre-loxP system (Fig. 4A). When ubiquitous or tissue-specific promoter driven Cre is fused with the estrogen receptor containing a mutated ligand binding domain (ER-LBD), which is normally bound by heat shock protein 90 (HSP90), Cre-ER-HSP90 complex would be prevented from entering the nucleus. Once bound by the hormone (such as estrogen) or synthetic analogs (such as tamoxifen, T, or 4-hydoxytamoxifen, 4-OHT), ER will be released from HSP90. This enables the nuclear translocation of Cre-ERT complex and the following interaction between Cre and loxP sites [8, 32].

Another inducible system is tetracycline inducible Cre-loxP system, also known as doxycycline (dox; a tetracycline derivative)-inducible Cre system. This system has two mode: tet-on (Fig. 4B) and tet-off (Fig. 4C), responsible for the activation and inactivation of Cre gene, respectively [72, 73]. There are three elements orchestrating to control Cre expression in this system: reverse tetracycline-controlled transactivator (rtTA), tetracycline-controlled transactivator (tTA) and tetracycline responsive element (TRE), also named as a tetracycline operon (TetO). In tet-on system, ubiquitous or tissue-specific promoter driven rtTA binds to dox to turn on the transcription of Cre gene (Fig. 4B). On the contrary, in tet-off system, tTA binds to dox to turn off the transcription of Cre gene (Fig. 4C).

Figure 4. Operational principles of inducible tissue-specific Cre-loxP system [7]. (A) Tamoxifen-inducible Cre-loxP system with estrogen receptor (ER) fused to Cre (CreER).
When tamoxifen is supplemented to bind to ER, Cre will translocate into nucleus to mediate the excision target gene Y. (B) Tetracycline (Tet)-on Cre-loxP system. Without dox, inactivated rtTA cannot activate the tetO7 (7 repeats of a 19 nuclotide tetO minimal promoter) for Cre expression. Upon the supplementation of dox, activated rtTA binds to tetO7 to initiate the transcription of Cre gene. (C) Tet-off Cre-loxP system. In the absence of dox, tTA is able to bind to tetO7 to activate Cre expression. Following the administration of dox, tTA will be silenced as well as lose the ability to bind to tetO7 and activate Cre transcription.

So far, a huge number of Cre transgenic lines have been established to combine with GOI loxP lines to generate conditional knockout mice or cell lines at the desired period and tissues in vitro or in vivo. Given that it is time and labor consuming to use Cre transgenic mice lines, viral vectors are convenient and versatile tools for the expression of Cre in certain cells or tissues, such as adeno-associated viral (AAV) vectors, as well as cell lines, such as adenovirus (Ad).


The Cre-loxP system, especially inducible tissue-specific knockout and viral vector-mediated Cre expression, has been highly utilized in genetics and cell biology research. Nevertheless, it seems that Cre-loxP system will continue to be prevalent in current and future research studies. GeneMedi is proficient in viral vector development and offers kinds of viral vector-based Cre tools, we can provide the best services and products if required.


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