In Vivo Genetic Strategies for the Specific Lineage Tracing of Stem Cells

Author(s): Hong Fan, Xinyu Liu, Yahui Shen, Siwei Chen, Yu Huan, Junjia Shan, Chengji Zhou, Shengxi Wu, Zifeng Zhang*, Yazhou Wang*.

Journal Name: Current Stem Cell Research & Therapy

Volume 14 , Issue 3 , 2019

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Background: Characterization of the fate changes of stem cells is essential to understand the roles of certain stem cells both during development and in diseases, such as cancer. In the past two decades, more and more importance has been paid to the studies of in vivo lineage tracing, because they could authentically reveal the differentiation, migration and even proliferation of stem cells. However, specific genetic tools have only been developed until recently.

Objective: To summarize the progresses of genetic tools for specific lineage tracing with emphasis on their applications in investigating the stem cell niche signals.

Results: Three major genetic strategies have been reviewed according to the development of technique, particularly the advantages and disadvantages of individual methods.

Conclusion: In vivo specific lineage tracing of stem cells could be achieved by comprehensive application of multiple genetic tools.

Keywords: Genetic tools, lineage tracing, stem cells, site-specific recombinases, reporter alleles, niche signals.

Stent GS, Weisblat DA. Cell lineage in the development of invertebrate nervous systems. Annu Rev Neurosci 1985; 8: 45-70.
Lanciego JL, Wouterlood FG. A half century of experimental neuroanatomical tracing. J Chem Neuroanat 2011; 42(3): 157-83.
Chalfie M, Tu Y, Euskirchen G, et al. Green fluorescent protein as a marker for gene expression. Science 1994; 263(5148): 802-5.
Heim R, Tsien RY. Engineering green fluorescent protein for improved brightness, longer wavelengths and fluorescence resonance energy transfer. Curr Biol 1996; 6(2): 178-82.
Ryu BY, Orwig KE, Avarbock MR, et al. Stem cell and niche development in the postnatal rat testis. Dev Biol 2003; 263(2): 253-63.
Wallenfang MR, Nayak R, DiNardo S. Dynamics of the male germline stem cell population during aging of Drosophila melanogaster. Aging Cell 2006; 5(4): 297-304.
Margolis J, Spradling A. Identification and behavior of epithelial stem cells in the Drosophila ovary. Development 1995; 121(11): 3797-807.
Rulands S, Simons BD. Tracing cellular dynamics in tissue development, maintenance and disease. Curr Opin Cell Biol 2016; 43: 38-45.
Solek CM, Ekker M. Cell lineage tracing techniques for the study of brain development and regeneration. Int J Dev Neurosci 2012; 30(7): 560-9.
Pfeiffer BD, Ngo TT, Hibbard KL, et al. Refinement of tools for targeted gene expression in Drosophila. Genetics 2010; 186(2): 735-55.
Petitclerc D, Attal J, Theron MC, et al. The effect of various introns and transcription terminators on the efficiency of expression vectors in various cultured cell lines and in the mammary gland of transgenic mice. J Biotechnol 1995; 40(3): 169-78.
Booker-Dwyer T, Hirsh S, et al. A unique cell population in the mouse olfactory bulb displays nuclear beta-catenin signaling during development and olfactory sensory neuron regeneration. Dev Neurobiol 2008; 68(7): 859-69.
Wang YZ, Yamagami T, Gan Q, et al. Canonical Wnt signaling promotes the proliferation and neurogenesis of peripheral olfactory stem cells during postnatal development and adult regeneration. J Cell Sci 2011; 124(Pt 9): 1553-63.
Capecchi MR. Altering the genome by homologous recombination. Science 1989; 244(4910): 1288-92.
Rong YS. Gene targeting by homologous recombination: A powerful addition to the genetic arsenal for Drosophila geneticists. Biochem Biophys Res Commun 2002; 297(1): 1-5.
Yang J, Liu X, Zhang X, et al. Predominant neuronal differentiation of Olig1+ neural progenitors in forebrain cortex biased by beta-catenin over-expression. Neurosci Lett 2016; 622: 19-23.
Chappell SA, Edelman GM, Mauro VP. A 9-nt segment of a cellular mRNA can function as an internal ribosome entry site (IRES) and when present in linked multiple copies greatly enhances IRES activity. Proc Natl Acad Sci USA 2000; 97(4): 1536-41.
Pelletier J, Sonenberg N. Internal initiation of translation of eukaryotic mRNA directed by a sequence derived from poliovirus RNA. Nature 1988; 334(6180): 320-5.
Ryan MD, King AM, Thomas GP. Cleavage of foot-and-mouth disease virus polyprotein is mediated by residues located within a 19 amino acid sequence. J Gen Virol 1991; 72(Pt11): 2727-32.
Kim JH, Lee SR, Li LH, et al. High cleavage efficiency of a 2A peptide derived from porcine teschovirus-1 in human cell lines, zebrafish and mice. PLoS One 2011; 6(4): e18556.
Trichas G, Begbie J, Srinivas S. Use of the viral 2A peptide for bicistronic expression in transgenic mice. BMC Biol 2008; 6(4): 40.
Heintz N. BAC to the future: The use of bac transgenic mice for neuroscience research. Nat Rev Neurosci 2001; 2(12): 861-70.
Venken KJ, He Y, Hoskins RA, et al. P[acman]: A BAC transgenic platform for targeted insertion of large DNA fragments in D.melanogaster. Science 2006; 314(5806): 1747-51.
Yang XW, Model P, Heintz N. Homologous recombination based modification in Escherichia coli and germline transmission in transgenic mice of a bacterial artificial chromosome. Nat Biotechnol 1997; 15(9): 859-65.
Sjulson L, Cassataro D, DasGupta S, et al. Cell-Specific Targeting of Genetically Encoded Tools for Neuroscience. Annu Rev Genet 2016; 50: 571-94.
Rong YS, Golic KG. Gene targeting by homologous recombination in Drosophila. Science 2000; 288(5473): 2013-8.
Crittenden JR, Lacey CJ, Lee T, et al. Severe drug-induced repetitive behaviors and striatal overexpression of VAChT in ChAT-ChR2-EYFP BAC transgenic mice. Front Neural Circuits 2014; 8: 57.
Orban PC, Chui D, Marth JD. Tissue- and site-specific DNA recombination in transgenic mice. Proc Natl Acad Sci USA 1992; 89(15): 6861-5.
Golic KG, Lindquist S. The FLP recombinase of yeast catalyzes site-specific recombination in the Drosophila genome. Cell 1989; 59(3): 499-509.
Chuang K, Nguyen E, Sergeev Y, et al. Novel Heterotypic rox sites for combinatorial dre recombination strategies. G3 (Bethesda) 2015; 6(3): 559-71.
Kim WI, Wiesner SM, Largaespada DA. Vav promoter-tTA conditional transgene expression system for hematopoietic cells drives high level expression in developing B and T cells. Exp Hematol 2007; 35(8): 1231-9.
Hsu YC. Theory and practice of lineage tracing. Stem Cells 2015; 33(11): 3197-204.
Barker N, van Es JH, Kuipers J, et al. Identification of stem cells in small intestine and colon by marker gene Lgr5. Nature 2007; 449(7165): 1003-7.
Tata PR, Mou H, Pardo-Saganta A, et al. Dedifferentiation of committed epithelial cells into stem cells in vivo. Nature 2013; 503(7475): 218-23.
Webster NJ, Green S, Jin JR, et al. The hormone-binding domains of the estrogen and glucocorticoid receptors contain an inducible transcription activation function. Cell 1988; 54(2): 199-207.
Danielian PS, Muccino D, Rowitch DH, et al. Modification of gene activity in mouse embryos in utero by a tamoxifen-inducible form of Cre recombinase. Curr Biol 1998; 8(24): 1323-6.
Nakagawa T, Nabeshima Y, Yoshida S. Functional identification of the actual and potential stem cell compartments in mouse spermatogenesis. Dev Cell 2007; 12(2): 195-206.
Clayton E, Doupe DP, Klein AM, et al. A single type of progenitor cell maintains normal epidermis. Nature 2007; 446(7132): 185-9.
McGill BE, Barve RA, Maloney SE, et al. Abnormal microglia and enhanced inflammation-related gene transcription in mice with conditional deletion of Ctcf in Camk2a-Cre-expressing neurons. J Neurosci 2018; 38(1): 200-19.
Ootani A, Li X, Sangiorgi E, et al. Sustained in vitro intestinal epithelial culture within a Wnt-dependent stem cell niche. Nat Med 2009; 15(6): 701-6.
de Lau W, Barker N, Low TY, et al. Lgr5 homologues associate with Wnt receptors and mediate R-spondin signalling. Nature 2011; 476(7360): 293-7.
Lee J, Platt KA, Censullo P, et al. Gli1 is a target of Sonic hedgehog that induces ventral neural tube development. Development 1997; 124(13): 2537-52.
Snippert HJ, van der Flier LG, Sato T, et al. Intestinal crypt homeostasis results from neutral competition between symmetrically dividing Lgr5 stem cells. Cell 2010; 143(1): 134-44.
Blaas L, Pucci F, Messal HA, et al. Lgr6 labels a rare population of mammary gland progenitor cells that are able to originate luminal mammary tumours. Nat Cell Biol 2016; 18(12): 1346-56.
Peng YC, Levine CM, Zahid S, et al. Sonic hedgehog signals to multiple prostate stromal stem cells that replenish distinct stromal subtypes during regeneration. Proc Natl Acad Sci USA 2013; 110(51): 20611-6.
Basak O, Giachino C, Fiorini E, Macdonald HR, Taylor V. Neurogenic subventricular zone stem/progenitor cells are Notch1-dependent in their active but not quiescent state. J Neurosci 2012; 32(16): 5654-66.
Livet J, Weissman TA, Kang H, et al. Transgenic strategies for combinatorial expression of fluorescent proteins in the nervous system. Nature 2007; 450(7166): 56-62.
Weissman TA, Sanes JR, Lichtman JW, et al. Generating and imaging multicolor Brainbow mice. Cold Spring Harb Protoc 2011; 2011(7): 763-9.
Weissman TA, Sanes JR, Lichtman JW, et al. Generation and imaging of Brainbow mice. Cold Spring Harb Protoc 2011; 2011(7): 851-6.
Branda CS, Dymecki SM. Talking about a revolution: The impact of site-specific recombinases on genetic analyses in mice. Dev Cell 2004; 6(1): 7-28.
Albert H, Dale EC, Lee E, et al. Site-specific integration of DNA into wild-type and mutant lox sites placed in the plant genome. Plant J 1995; 7(4): 649-59.
Rinkevich Y, Lindau P, Ueno H, et al. Germ-layer and lineage-restricted stem/progenitors regenerate the mouse digit tip. Nature 2011; 476(7361): 409-13.
Yanai H, Tanaka T, Ueno H. Multicolor lineage tracing methods and intestinal tumors. J Gastroenterol 2013; 48(4): 423-33.
Weissman TA, Pan YA. Brainbow: New resources and emerging biological applications for multicolor genetic labeling and analysis. Genetics 2015; 199(2): 293-306.
Hsu YC, Pasolli HA, Fuchs E. Dynamics between stem cells, niche, and progeny in the hair follicle. Cell 2011; 144(1): 92-105.
Forni PE, Scuoppo C, Imayoshi I, et al. High levels of Cre expression in neuronal progenitors cause defects in brain development leading to microencephaly and hydrocephaly. J Neurosci 2006; 26(37): 9593-602.
Lee T, Luo L. Mosaic analysis with a repressible cell marker for studies of gene function in neuronal morphogenesis. Neuron 1999; 22(3): 451-61.
Shrestha BR, Grueber WB. Generation and staining of MARCM clones in Drosophila. Cold Spring Harb Protoc 2011; 2011(8): 973-9.
Gu H, Marth JD, Orban PC, et al. Deletion of a DNA polymerase beta gene segment in T cells using cell type-specific gene targeting. Science 1994; 265(5168): 103-6.
Lewandoski M. Conditional control of gene expression in the mouse. Nat Rev Genet 2001; 2(10): 743-55.
Espinosa JS, Tea JS, Luo L. Mosaic analysis with double markers (MADM) in mice. Cold Spring Harb Protoc 2014; 2014(2): 182-9.
Liu C, Sage JC, Miller MR, et al. Mosaic analysis with double markers reveals tumor cell of origin in glioma. Cell 2011; 146(2): 209-21.
Beattie R, Postiglione MP, Burnett LE, et al. Mosaic Analysis with Double Markers Reveals Distinct Sequential Functions of Lgl1 in Neural Stem Cells. Neuron 2017; 94(3): 517-33.
Casanova E, Lemberger T, Fehsenfeld S, et al. Alpha complementation in the Cre recombinase enzyme. Genesis 2003; 37(1): 25-9.
Wang P, Chen T, Sakurai K, et al. Intersectional Cre driver lines generated using split-intein mediated split-Cre reconstitution. Sci Rep 2012; 2: 497.
Anraku Y, Mizutani R, Satow Y. Protein splicing: its discovery and structural insight into novel chemical mechanisms. IUBMB Life 2005; 57(8): 563-74.
Ge J, Wang L, Yang C, et al. Intein-mediated Cre protein assembly for transgene excision in hybrid progeny of transgenic Arabidopsis. Plant Cell Rep 2016; 35(10): 2045-53.
Beckervordersandforth R, Deshpande A, Schaffner I, et al. In vivo targeting of adult neural stem cells in the dentate gyrus by a split-cre approach. Stem Cell Reports 2014; 2(2): 153-62.
Madisen L, Garner AR, Shimaoka D, et al. Transgenic mice for intersectional targeting of neural sensors and effectors with high specificity and performance. Neuron 2015; 85(5): 942-58.
Zeng H, Horie K, Madisen L, et al. An inducible and reversible mouse genetic rescue system. PLoS Genet 2008; 4(5): e1000069.
Loulier K, Barry R, Mahou P, et al. Multiplex cell and lineage tracking with combinatorial labels. Neuron 2014; 81(3): 505-20.
Allen WE, Luo L. Intersectional illumination of neural circuit function. Neuron 2015; 85(5): 889-92.

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Year: 2019
Page: [230 - 238]
Pages: 9
DOI: 10.2174/1574888X13666180726110138
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