Pancreas-Specific Cre Driver Lines and Considerations for Their Prudent Use
2013; Cell Press; Volume: 18; Issue: 1 Linguagem: Inglês
10.1016/j.cmet.2013.06.011
ISSN1932-7420
AutoresMark A. Magnuson, Anna B. Osipovich,
Tópico(s)CRISPR and Genetic Engineering
ResumoCre/LoxP has broad utility for studying the function, development, and oncogenic transformation of pancreatic cells in mice. Here we provide an overview of the Cre driver lines that are available for such studies. We discuss how variegated expression, transgene silencing, and recombination in undesired cell types have conspired to limit the performance of these lines, sometimes leading to serious experimental concerns. We also discuss preferred strategies for achieving high-fidelity driver lines and remind investigators of the continuing need for caution when interpreting results obtained from any Cre/LoxP-based experiment performed in mice. Cre/LoxP has broad utility for studying the function, development, and oncogenic transformation of pancreatic cells in mice. Here we provide an overview of the Cre driver lines that are available for such studies. We discuss how variegated expression, transgene silencing, and recombination in undesired cell types have conspired to limit the performance of these lines, sometimes leading to serious experimental concerns. We also discuss preferred strategies for achieving high-fidelity driver lines and remind investigators of the continuing need for caution when interpreting results obtained from any Cre/LoxP-based experiment performed in mice. Cre/LoxP is a site-specific recombinase (SSR) system of proven utility. As for many tissues, Cre/LoxP is frequently used to study the function, development, and neoplasia of exocrine and endocrine cells in the pancreas. The widespread use of Cre/LoxP arises from its ability to conditionally eliminate or activate expression of genes in a cell-type- and/or temporal-specific manner, thereby enabling the cell-, tissue-, and/or developmental-stage-specific functions of genes to be explored within animal models. While Cre/LoxP is most commonly used in mice, it and two other SSR systems, Flp/FRT and Dre/Rox, also have utility in other model organisms (Hoess et al., 1982Hoess R.H. Ziese M. Sternberg N. P1 site-specific recombination: nucleotide sequence of the recombining sites.Proc. Natl. Acad. Sci. USA. 1982; 79: 3398-3402Crossref PubMed Google Scholar, McLeod et al., 1986McLeod M. Craft S. Broach J.R. Identification of the crossover site during FLP-mediated recombination in the Saccharomyces cerevisiae plasmid 2 microns circle.Mol. Cell. Biol. 1986; 6: 3357-3367Crossref PubMed Scopus (0) Google Scholar, Sauer and McDermott, 2004Sauer B. McDermott J. DNA recombination with a heterospecific Cre homolog identified from comparison of the pac-c1 regions of P1-related phages.Nucleic Acids Res. 2004; 32: 6086-6095Crossref PubMed Scopus (44) Google Scholar). Cre, Flp, and Dre, members of the λ integrase superfamily of site-specific recombinases, were cloned from different organisms. Cre is encoded by bacteriophage P1, Flp by the budding yeast Saccharomyces cerevisiae, and Dre, the most recently described SSR, by bacteriophage D6. All three recombinases function as homotetramers and have 34 bp DNA recognition sequences called LoxP, FRT, and Rox, respectively. The small size of these recombination recognition sites enables them to be readily placed within genes where they, in combination with Cre, Flp, or Dre, enable gene deletions, insertions, inversions, or translocations. Over the past two decades, several useful Cre and Flp derivatives have been described. Undoubtedly, the most useful variant for Cre has been CreER, which prevents Cre from entering the nucleus in the absence of tamoxifen due to the addition of a mutated version of the estrogen receptor (ER) hormone-binding domain (Feil et al., 1996Feil R. Brocard J. Mascrez B. LeMeur M. Metzger D. Chambon P. Ligand-activated site-specific recombination in mice.Proc. Natl. Acad. Sci. USA. 1996; 93: 10887-10890Crossref PubMed Scopus (449) Google Scholar). CreER enables temporal control of Cre recombination. However, some investigators have found that efficient tamoxifen-induced recombination is not always achieved, thereby requiring that multiple doses of tamoxifen be administered, and that recombination by CreER may occur weeks after tamoxifen dosing (Reinert et al., 2012Reinert R.B. Kantz J. Misfeldt A.A. Poffenberger G. Gannon M. Brissova M. Powers A.C. Tamoxifen-Induced Cre-loxP Recombination Is Prolonged in Pancreatic Islets of Adult Mice.PLoS ONE. 2012; 7: e33529Crossref PubMed Scopus (22) Google Scholar). Another useful derivative of Cre is GFPCre, which is a fusion with green fluorescent protein (GFP) that makes it easy to directly identify cells that express Cre (Gagneten et al., 1997Gagneten S. Le Y. Miller J. Sauer B. Brief expression of a GFP cre fusion gene in embryonic stem cells allows rapid retrieval of site-specific genomic deletions.Nucleic Acids Res. 1997; 25: 3326-3331Crossref PubMed Scopus (67) Google Scholar). For Flp, the most useful derivatives are enhanced Flp (FlpE), which improves thermostabilty, and Flpo, a codon-optimized variant that improves expression (Buchholz et al., 1998Buchholz F. Angrand P.O. Stewart A.F. Improved properties of FLP recombinase evolved by cycling mutagenesis.Nat. Biotechnol. 1998; 16: 657-662Crossref PubMed Scopus (239) Google Scholar, Raymond and Soriano, 2007Raymond C.S. Soriano P. High-efficiency FLP and PhiC31 site-specific recombination in mammalian cells.PLoS ONE. 2007; 2: e162Crossref PubMed Scopus (141) Google Scholar). Although both Flp and Dre also have utility in the mouse, particularly when used in combination with Cre, hereafter we focus our comments on Cre. As illustrated in Figure 1, the conditional inactivation of a gene using Cre/LoxP requires two different genetic components: (1) a Cre driver line and (2) a target allele in which a gene segment, usually containing one or more exons, has been flanked with tandemly oriented LoxP sites (a so-called floxed allele) (Gu et al., 1994Gu H. Marth J.D. Orban P.C. Mossmann H. Rajewsky K. Deletion of a DNA polymerase beta gene segment in T cells using cell type-specific gene targeting.Science. 1994; 265: 103-106Crossref PubMed Google Scholar, Orban et al., 1992Orban P.C. Chui D. Marth J.D. Tissue- and site-specific DNA recombination in transgenic mice.Proc. Natl. Acad. Sci. USA. 1992; 89: 6861-6865Crossref PubMed Scopus (326) Google Scholar). Similarly, the required components to conditionally activate gene expression are (1) a Cre driver line and (2) an allele that has been engineered to contain a lox-stop-lox (LSL) sequence upstream of the coding sequences to be expressed. The ubiquitously expressed ROSA26 gene locus has been used extensively for this purpose (Soriano, 1999Soriano P. Generalized lacZ expression with the ROSA26 Cre reporter strain.Nat. Genet. 1999; 21: 70-71Crossref PubMed Scopus (2997) Google Scholar). Indeed, Cre-dependent activation of ROSA26 alleles containing an LSL upstream of β-galactosidase or different fluorescent proteins (e.g., Gt[ROSA]26Sortm1Sor, Gt[ROSA]26Sortm1[EYFP]Cos, and Gt[ROSA]26Sortm2Sho; Mao et al., 2001Mao X. Fujiwara Y. Chapdelaine A. Yang H. Orkin S.H. Activation of EGFP expression by Cre-mediated excision in a new ROSA26 reporter mouse strain.Blood. 2001; 97: 324-326Crossref PubMed Scopus (162) Google Scholar, Soriano, 1999Soriano P. Generalized lacZ expression with the ROSA26 Cre reporter strain.Nat. Genet. 1999; 21: 70-71Crossref PubMed Scopus (2997) Google Scholar, Srinivas et al., 2001Srinivas S. Watanabe T. Lin C.S. William C.M. Tanabe Y. Jessell T.M. Costantini F. Cre reporter strains produced by targeted insertion of EYFP and ECFP into the ROSA26 locus.BMC Dev. Biol. 2001; 1: 4Crossref PubMed Google Scholar) has become a standard tool in the Cre/LoxP tool chest. Not only do these alleles enable cell lineage tracing, which is fundamentally important in studies of developmental biology, they can also be used to readily assess both the sites and efficiency of Cre-mediated recombination (Sato et al., 2000Sato M. Yasuoka Y. Kodama H. Watanabe T. Miyazaki J.I. Kimura M. New approach to cell lineage analysis in mammals using the Cre-loxP system.Mol. Reprod. Dev. 2000; 56: 34-44Crossref PubMed Scopus (22) Google Scholar). For many years, the development of new floxed alleles was the limiting factor in using Cre/LoxP to perform a cell- or tissue-specific gene knockout study. This was due to the need to perform gene targeting in mouse embryonic stem cells (mESCs) and then to introduce the mutant allele into the germline of mice. However, as a result of the combined efforts of many individual laboratories and the large-scale Knockout Mouse Project (KOMP) (Austin et al., 2004Austin C.P. Battey J.F. Bradley A. Bucan M. Capecchi M. Collins F.S. Dove W.F. Duyk G. Dymecki S. Eppig J.T. et al.The knockout mouse project.Nat. Genet. 2004; 36: 921-924Crossref PubMed Scopus (343) Google Scholar), the number of floxed alleles available to investigators has skyrocketed. In contrast, there are fewer truly accurate and reliable Cre driver lines, as we discuss in detail below. Optimal use of the Cre/LoxP depends greatly on the functional precision of the Cre driver line, which is determined in large part by the method used to derive the line. Moreover, the functionality of some lines, particularly those made by pronuclear DNA microinjection of short transgenes, can be impaired or destroyed due to transgene silencing as the lines are passaged. All of these factors argue for caution when acquiring and using lines, especially those that do not have a proven history of use. Indeed, when using any line, investigators need to remain keenly aware of the limitations of Cre/LoxP itself, in addition to the known deficiencies of a given line, before drawing scientific conclusions from any experiments that utilize this method. An almost certainly incomplete list of Cre driver lines that have been used in studies of pancreas development and/or function is shown in Table 1. These 79 driver lines, which were identified based on either published descriptions or the Beta Cell Biology Consortium website (www.betacell.org), have been arbitrarily subdivided into four partially overlapping categories based on the cell types in which Cre is expressed. Together, these lines have utilized the promoters of 32 different genes to direct the expression of Cre.Table 1Pancreas-Specific Cre Driver LinesMGI NameCommon NameTypeDriver Gene (Size if Applicable or Known)/Expression Site(s) in PancreasReferenceEndocrine Cell SpecificTg(Ins2-cre)1HeedRIP1-Cretransgenerat Ins2 (0.7 kb)/β cellsAhlgren et al., 1998Ahlgren U. Jonsson J. Jonsson L. Simu K. Edlund H. beta-cell-specific inactivation of the mouse Ipf1/Pdx1 gene results in loss of the beta-cell phenotype and maturity onset diabetes.Genes Dev. 1998; 12: 1763-1768Crossref PubMed Google ScholarTg(Ins2-cre)6FcbRIP-Cretransgenerat Ins2 (0.45 kb)/β cellsRay et al., 1999Ray M.K. Fagan S.P. Moldovan S. DeMayo F.J. Brunicardi F.C. Development of a transgenic mouse model using rat insulin promoter to drive the expression of CRE recombinase in a tissue-specific manner.Int. J. Pancreatol. 1999; 25: 157-163PubMed Google ScholarTg(Ins2-cre)7FcbRIP-Cretransgenerat Ins2 (0.45 kb)/β cellsRay et al., 1999Ray M.K. Fagan S.P. Moldovan S. DeMayo F.J. Brunicardi F.C. Development of a transgenic mouse model using rat insulin promoter to drive the expression of CRE recombinase in a tissue-specific manner.Int. J. Pancreatol. 1999; 25: 157-163PubMed Google ScholarTg(Ins2-cre)23HerrRIP-Cretransgenerat Ins2 (0.60 kb)/β cellsHerrera, 2000Herrera P.L. Adult insulin- and glucagon-producing cells differentiate from two independent cell lineages.Development. 2000; 127: 2317-2322Crossref PubMed Google ScholarTg(Ins2-cre)25MgnRIP-Cretransgenerat Ins2 (0.66 kb)/β cellsPostic et al., 1999Postic C. Shiota M. Niswender K.D. Jetton T.L. Chen Y. Moates J.M. Shelton K.D. Lindner J. Cherrington A.D. Magnuson M.A. Dual roles for glucokinase in glucose homeostasis as determined by liver and pancreatic beta cell-specific gene knock-outs using Cre recombinase.J. Biol. Chem. 1999; 274: 305-315Crossref PubMed Scopus (590) Google ScholarTg(Ins2-cre/ERT)1DamRIP-CreERtransgenerat Ins2 (0.66 kb)/β cellsDor et al., 2004Dor Y. Brown J. Martinez O.I. Melton D.A. Adult pancreatic beta-cells are formed by self-duplication rather than stem-cell differentiation.Nature. 2004; 429: 41-46Crossref PubMed Scopus (1252) Google ScholarTg(Ins2-cre)1DhRIP7-Cretransgenerat Ins2 (10 kb)/β cellsCrabtree et al., 2003Crabtree J.S. Scacheri P.C. Ward J.M. McNally S.R. Swain G.P. Montagna C. Hager J.H. Hanahan D. Edlund H. Magnuson M.A. et al.Of mice and MEN1: Insulinomas in a conditional mouse knockout.Mol. Cell. Biol. 2003; 23: 6075-6085Crossref PubMed Scopus (111) Google ScholarTg(INS-cre)2RmsHIP-Cretransgenehuman INS (1.9 kb)/β cellsHamilton-Williams et al., 2003Hamilton-Williams E.E. Palmer S.E. Charlton B. Slattery R.M. Beta cell MHC class I is a late requirement for diabetes.Proc. Natl. Acad. Sci. 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Adult insulin- and glucagon-producing cells differentiate from two independent cell lineages.Development. 2000; 127: 2317-2322Crossref PubMed Google ScholarTg(Gcg-cre)1SlibGlu-Cretransgenerat Gcg (2.3 kb)/α cellsShen et al., 2009Shen H.C. Adem A. Ylaya K. Wilson A. He M. Lorang D. Hewitt S.M. Pechhold K. Harlan D.M. Lubensky I.A. et al.Deciphering von Hippel-Lindau (VHL/Vhl)-associated pancreatic manifestations by inactivating Vhl in specific pancreatic cell populations.PLoS ONE. 2009; 4: e4897Crossref PubMed Scopus (18) Google ScholarTg(Ppy-cre)1HerrPP-Cretransgenerat Ppy (0.6 kb)/PP cellsHerrera, 2000Herrera P.L. Adult insulin- and glucagon-producing cells differentiate from two independent cell lineages.Development. 2000; 127: 2317-2322Crossref PubMed Google ScholarSsttm1(cre/ERT2)ZjhSst-CreERknock-inmouse Sst/δ cellsTaniguchi et al., 2011Taniguchi H. He M. Wu P. Kim S. Paik R. Sugino K. Kvitsiani D. Fu Y. Lu J. 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