REVIEW

Dissection of gene function at clonal level using mosaic analysis with double markers

  • Simon HIPPENMEYER
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  • IST Austria (Institute of Science and Technology Austria), Am Campus 1, A-3400 Klosterneuburg, Austria

Received date: 11 May 2013

Accepted date: 08 Aug 2013

Published date: 01 Dec 2013

Copyright

2014 Higher Education Press and Springer-Verlag Berlin Heidelberg

Abstract

MADM (Mosaic Analysis with Double Markers) technology offers a genetic approach in mice to visualize and concomitantly manipulate genetically defined cells at clonal level and single cell resolution. MADM employs Cre recombinase/loxP-dependent interchromosomal mitotic recombination to reconstitute two split marker genes—green GFP and red tdTomato — and can label sparse clones of homozygous mutant cells in one color and wild-type cells in the other color in an otherwise unlabeled background. At present, major MADM applications include lineage tracing, single cell labeling, conditional knockouts in small populations of cells and induction of uniparental chromosome disomy to assess effects of genomic imprinting. MADM can be applied universally in the mouse with the sole limitation being the specificity of the promoter controlling Cre recombinase expression. Here I review recent developments and extensions of the MADM technique and give an overview of the major discoveries and progresses enabled by the implementation of the novel genetic MADM tools.

Cite this article

Simon HIPPENMEYER . Dissection of gene function at clonal level using mosaic analysis with double markers[J]. Frontiers in Biology, 2013 , 8(6) : 557 -568 . DOI: 10.1007/s11515-013-1279-6

Acknowledgements

I thank L. Luo and H. Zong for continued discussions about MADM and G. Arque for helpful comments on the manuscript. This work was supported by IST Austria institutional funds.
Compliance with ethics guidelines
Simon Hippenmeyer declares that he has no conflict of interest and that all IST Austria institutional and national guidelines for the care and use of laboratory animals were followed.
1
Armakolas A, Klar A J (2006). Cell type regulates selective segregation of mouse chromosome 7 DNA strands in mitosis. Science, 311(5764): 1146-1149

DOI PMID

2
Ayala R, Shu T, Tsai L H (2007). Trekking across the brain: the journey of neuronal migration. Cell, 128(1): 29-43

DOI PMID

3
Badea T C, Wang Y, Nathans J (2003). A noninvasive genetic/pharmacologic strategy for visualizing cell morphology and clonal relationships in the mouse. J Neurosci, 23(6): 2314-2322

4
Barlow D P (2011). Genomic imprinting: a mammalian epigenetic discovery model. Annu Rev Genet, 45(1): 379-403

DOI PMID

5
Bartolomei M S, Ferguson-Smith A C (2011). Mammalian genomic imprinting. Cold Spring Harb Perspect Biol, 3(7): 3

DOI PMID

6
Bi W, Yan J, Stankiewicz P, Park S S, Walz K, Boerkoel C F, Potocki L, Shaffer L G, Devriendt K, Nowaczyk M J, Inoue K, Lupski J R (2002). Genes in a refined Smith-Magenis syndrome critical deletion interval on chromosome 17p11.2 and the syntenic region of the mouse. Genome Res, 12(5): 713-728

DOI PMID

7
Blair S S (2003). Genetic mosaic techniques for studying Drosophila development. Development, 130(21): 5065-5072

DOI PMID

8
Bonaguidi M A, Wheeler M A, Shapiro J S, Stadel R P, Sun G J, Ming G L, Song H (2011). In vivo clonal analysis reveals self-renewing and multipotent adult neural stem cell characteristics. Cell, 145(7): 1142-1155

DOI PMID

9
Branda C S, Dymecki S M (2004). Talking about a revolution: The impact of site-specific recombinases on genetic analyses in mice. Dev Cell, 6(1): 7-28

DOI PMID

10
Brennand K, Huangfu D, Melton D (2007). All beta cells contribute equally to islet growth and maintenance. PLoS Biol, 5(7): e163

DOI PMID

11
Buckingham M E, Meilhac S M (2011). Tracing cells for tracking cell lineage and clonal behavior. Dev Cell, 21(3): 394-409

DOI PMID

12
Cajal S R y (1911). Histology of the Nervous System of Man and Vertebrates. Oxford University Press, Inc, Oxford 1995 Translation

13
Cepko C, Ryder E F, Austin C P, Walsh C, Fekete D M (1995). Lineage analysis using retrovirus vectors. Methods Enzymol, 254: 387-419

DOI PMID

14
Chow B Y, Han X, Boyden E S (2012). Genetically encoded molecular tools for light-driven silencing of targeted neurons. Prog Brain Res, 196: 49-61

DOI PMID

15
Cowan W M (1998). The emergence of modern neuroanatomy and developmental neurobiology. Neuron, 20(3): 413-426

DOI PMID

16
De Paola V, Arber S, Caroni P (2003). AMPA receptors regulate dynamic equilibrium of presynaptic terminals in mature hippocampal networks. Nat Neurosci, 6(5): 491-500

PMID

17
Desgraz R, Herrera P L (2009). Pancreatic neurogenin 3-expressing cells are unipotent islet precursors. Development, 136(21): 3567-3574

DOI PMID

18
Dessaud E, Yang L L, Hill K, Cox B, Ulloa F, Ribeiro A, Mynett A, Novitch B G, Briscoe J (2007). Interpretation of the sonic hedgehog morphogen gradient by a temporal adaptation mechanism. Nature, 450(7170): 717-720

DOI PMID

19
Dymecki S M, Kim J C (2007). Molecular neuroanatomy’s “Three Gs”: a primer. Neuron, 54(1): 17-34

DOI PMID

20
Espinosa J S, Luo L (2008). Timing neurogenesis and differentiation: insights from quantitative clonal analyses of cerebellar granule cells. J Neurosci, 28: 2301-2312

21
Espinosa J S, Wheeler D G, Tsien R W, Luo L (2009). Uncoupling dendrite growth and patterning: single-cell knockout analysis of NMDA receptor 2B. Neuron, 62(2): 205-217

DOI PMID

22
Feil R, Brocard J, Mascrez B, LeMeur M, Metzger D, Chambon P (1996). Ligand-activated site-specific recombination in mice. Proc Natl Acad Sci USA, 93(20): 10887-10890

DOI PMID

23
Feinberg A P (2007). Phenotypic plasticity and the epigenetics of human disease. Nature, 447(7143): 433-440

DOI PMID

24
Feng G, Mellor R H, Bernstein M, Keller-Peck C, Nguyen Q T, Wallace M, Nerbonne J M, Lichtman J W, Sanes J R (2000). Imaging neuronal subsets in transgenic mice expressing multiple spectral variants of GFP. Neuron, 28(1): 41-51

DOI PMID

25
Foo L C, Allen N J, Bushong E A, Ventura P B, Chung W S, Zhou L, Cahoy J D, Daneman R, Zong H, Ellisman M H, Barres B A (2011). Development of a method for the purification and culture of rodent astrocytes. Neuron, 71(5): 799-811

DOI PMID

26
Franco S J, Müller U (2013). Shaping our minds: stem and progenitor cell diversity in the mammalian neocortex. Neuron, 77(1): 19-34

DOI PMID

27
Gao P, Sultan K T, Zhang X J, Shi S H (2013). Lineage-dependent circuit assembly in the neocortex. Development, 140(13): 2645-2655

DOI PMID

28
Gorski J A, Talley T, Qiu M, Puelles L, Rubenstein J L, Jones K R (2002). Cortical excitatory neurons and glia, but not GABAergic neurons, are produced in the Emx1-expressing lineage. J Neurosci, 22: 6309-6314

29
Hallonet M E, Le Douarin N M (1993). Tracing neuroepithelial cells of the mesencephalic and metencephalic alar plates during cerebellar ontogeny in quail-chick chimaeras. Eur J Neurosci, 5(9): 1145-1155

DOI PMID

30
Hayashi S, McMahon A P (2002). Efficient recombination in diverse tissues by a tamoxifen-inducible form of Cre: a tool for temporally regulated gene activation/inactivation in the mouse. Dev Biol, 244(2): 305-318

DOI PMID

31
Hegemann P, Möglich A (2011). Channelrhodopsin engineering and exploration of new optogenetic tools. Nat Methods, 8(1): 39-42

DOI PMID

32
Hippenmeyer S, Johnson R L, Luo L (2013). Mosaic analysis with double markers reveals cell-type-specific paternal growth dominance. Cell Rep, 3: 960-967

33
Hippenmeyer S, Vrieseling E, Sigrist M, Portmann T, Laengle C, Ladle D R, Arber S (2005). A developmental switch in the response of DRG neurons to ETS transcription factor signaling. PLoS Biol, 3(5): e159

DOI PMID

34
Hippenmeyer S, Youn Y H, Moon H M, Miyamichi K, Zong H, Wynshaw-Boris A, Luo L (2010). Genetic mosaic dissection of Lis1 and Ndel1 in neuronal migration. Neuron, 68(4): 695-709

DOI PMID

35
Imayoshi I, Ohtsuka T, Metzger D, Chambon P, Kageyama R (2006). Temporal regulation of Cre recombinase activity in neural stem cells. Genesis, 44(5): 233-238

DOI PMID

36
Indra A K, Warot X, Brocard J, Bornert J M, Xiao J H, Chambon P, Metzger D (1999). Temporally-controlled site-specific mutagenesis in the basal layer of the epidermis: comparison of the recombinase activity of the tamoxifen-inducible Cre-ER(T) and Cre-ER(T2) recombinases. Nucleic Acids Res, 27(22): 4324-4327

DOI PMID

37
Jefferis G S, Livet J (2012). Sparse and combinatorial neuron labelling. Curr Opin Neurobiol, 22(1): 101-110

DOI PMID

38
Lao Z, Raju G P, Bai C B, Joyner A L (2012). MASTR: a technique for mosaic mutant analysis with spatial and temporal control of recombination using conditional floxed alleles in mice. Cell Rep, 2: 386-396

39
Lee T, Luo L (1999). Mosaic analysis with a repressible cell marker for studies of gene function in neuronal morphogenesis. Neuron, 22(3): 451-461

DOI PMID

40
Legué E, Joyner A L (2010). Genetic fate mapping using site-specific recombinases. Methods Enzymol, 477: 153-181

DOI PMID

41
Lehtinen M K, Walsh C A (2011). Neurogenesis at the brain-cerebrospinal fluid interface. Annu Rev Cell Dev Biol, 27(1): 653-679

DOI PMID

42
Lewandoski M (2001). Conditional control of gene expression in the mouse. Nat Rev Genet, 2(10): 743-755

DOI PMID

43
Liang H, Xiao G, Yin H, Hippenmeyer S, Horowitz J M, Ghashghaei H T (2013). Neural development is dependent on the function of specificity protein 2 in cell cycle progression. Development, 140(3): 552-561

DOI PMID

44
Liu C, Sage J C, Miller M R, Verhaak R G, Hippenmeyer S, Vogel H, Foreman O, Bronson R T, Nishiyama A, Luo L, Zong H (2011). Mosaic analysis with double markers reveals tumor cell of origin in glioma. Cell, 146(2): 209-221

DOI PMID

45
Liu P, Jenkins N A, Copeland N G (2002). Efficient Cre-loxP-induced mitotic recombination in mouse embryonic stem cells. Nat Genet, 30(1): 66-72

DOI PMID

46
Lui J H, Hansen D V, Kriegstein A R (2011). Development and evolution of the human neocortex. Cell, 146(1): 18-36

DOI PMID

47
Luo L (2007). Fly MARCM and mouse MADM: genetic methods of labeling and manipulating single neurons. Brain Res Brain Res Rev, 55(2): 220-227

DOI PMID

48
Mabb A M, Judson M C, Zylka M J, Philpot B D (2011). Angelman syndrome: insights into genomic imprinting and neurodevelopmental phenotypes. Trends Neurosci, 34(6): 293-303

DOI PMID

49
Madisen L, Zwingman T A, Sunkin S M, Oh S W, Zariwala H A, Gu H, Ng L L, Palmiter R D, Hawrylycz M J, Jones A R, Lein E S, Zeng H (2010). A robust and high-throughput Cre reporting and characterization system for the whole mouse brain. Nat Neurosci, 13(1): 133-140

DOI PMID

50
Marín O, Valiente M, Ge X, Tsai L H (2010). Guiding neuronal cell migrations. Cold Spring Harb Perspect Biol, 2(2): a001834

DOI PMID

51
McConnell S K (1988). Fates of visual cortical neurons in the ferret after isochronic and heterochronic transplantation. J Neurosci, 8: 945-974

52
Merkle F T, Mirzadeh Z, Alvarez-Buylla A (2007). Mosaic organization of neural stem cells in the adult brain. Science, 317(5836): 381-384

DOI PMID

53
Metzger D, Chambon P (2001). Site- and time-specific gene targeting in the mouse. Methods, 24(1): 71-80

DOI PMID

54
Ming G L, Song H (2011). Adult neurogenesis in the mammalian brain: significant answers and significant questions. Neuron, 70(4): 687-702

DOI PMID

55
Miyoshi G, Hjerling-Leffler J, Karayannis T, Sousa V H, Butt S J, Battiste J, Johnson J E, Machold R P, Fishell G (2010). Genetic fate mapping reveals that the caudal ganglionic eminence produces a large and diverse population of superficial cortical interneurons. J Neurosci, 30: 1582-1594

56
Morgan T H (1914). Mosaics and gynandromorphs in Drosophila. Proc Soc Exp Biol Med, 11(6): 171-172

DOI

57
Muzumdar M D, Luo L, Zong H (2007). Modeling sporadic loss of heterozygosity in mice by using mosaic analysis with double markers (MADM). Proc Natl Acad Sci USA, 104(11): 4495-4500

DOI PMID

58
Nelson S B, Sugino K, Hempel C M (2006). The problem of neuronal cell types: a physiological genomics approach. Trends Neurosci, 29(6): 339-345

DOI PMID

59
Nicholls R D, Knepper J L (2001). Genome organization, function, and imprinting in Prader-Willi and Angelman syndromes. Annu Rev Genomics Hum Genet, 2(1): 153-175

DOI PMID

60
Ninkovic J, Gotz M (2013). Fate specification in the adult brain-lessons for eliciting neurogenesis from glial cells. BioEssays, 35: 242-252

61
Novak A, Guo C, Yang W, Nagy A, Lobe C G (2000). Z/EG, a double reporter mouse line that expresses enhanced green fluorescent protein upon Cre-mediated excision. Genesis, 28(3-4): 147-155

DOI PMID

62
Petersen P H, Zou K, Hwang J K, Jan Y N, Zhong W (2002). Progenitor cell maintenance requires numb and numblike during mouse neurogenesis. Nature, 419(6910): 929-934

DOI PMID

63
Reiner O, Carrozzo R, Shen Y, Wehnert M, Faustinella F, Dobyns W B, Caskey C T, Ledbetter D H (1993). Isolation of a Miller-Dieker lissencephaly gene containing G protein beta-subunit-like repeats. Nature, 364(6439): 717-721

DOI PMID

64
Ross M E, Walsh C A (2001). Human brain malformations and their lessons for neuronal migration. Annu Rev Neurosci, 24(1): 1041-1070

DOI PMID

65
Sanes J R (1989). Analysing cell lineage with a recombinant retrovirus. Trends Neurosci, 12(1): 21-28

DOI PMID

66
Schnütgen F, Doerflinger N, Calléja C, Wendling O, Chambon P, Ghyselinck N B (2003). A directional strategy for monitoring Cre-mediated recombination at the cellular level in the mouse. Nat Biotechnol, 21(5): 562-565

DOI PMID

67
Shaner N C, Campbell R E, Steinbach P A, Giepmans B N, Palmer A E, Tsien R Y (2004). Improved monomeric red, orange and yellow fluorescent proteins derived from Discosoma sp. red fluorescent protein. Nat Biotechnol, 22(12): 1567-1572

DOI PMID

68
Smith G B, Fitzpatrick D (2012). Specifying cortical circuits: a role for cell lineage. Neuron, 75(1): 4-5

DOI PMID

69
Soriano P (1999). Generalized lacZ expression with the ROSA26 Cre reporter strain. Nat Genet, 21(1): 70-71

DOI PMID

70
Stern C (1936). Somatic Crossing over and Segregation in Drosophila Melanogaster. Genetics, 21(6): 625-730

PMID

71
Tasic B, Miyamichi K, Hippenmeyer S, Dani V S, Zeng H, Joo W, Zong H, Chen-Tsai Y, Luo L (2012). Extensions of MADM (mosaic analysis with double markers) in mice. PLoS ONE, 7(3): e33332

DOI PMID

72
Tronche F, Kellendonk C, Kretz O, Gass P, Anlag K, Orban P C, Bock R, Klein R, Schütz G (1999). Disruption of the glucocorticoid receptor gene in the nervous system results in reduced anxiety. Nat Genet, 23(1): 99-103

DOI PMID

73
Tsai J W, Chen Y, Kriegstein A R, Vallee R B (2005). LIS1 RNA interference blocks neural stem cell division, morphogenesis, and motility at multiple stages. J Cell Biol, 170(6): 935-945

DOI PMID

74
Walsh C, Cepko C L (1992). Widespread dispersion of neuronal clones across functional regions of the cerebral cortex. Science, 255(5043): 434-440

DOI PMID

75
Wingate R J, Hatten M E (1999). The role of the rhombic lip in avian cerebellum development. Development, 126(20): 4395-4404

PMID

76
Woodruff A, Xu Q, Anderson S A, Yuste R (2009). Depolarizing effect of neocortical chandelier neurons. Front Neural Circuits 3: 15.

77
Wynshaw-Boris A, Pramparo T, Youn Y H, Hirotsune S (2010). Lissencephaly: mechanistic insights from animal models and potential therapeutic strategies. Semin Cell Dev Biol, 21(8): 823-830

DOI PMID

78
Xu Q, Tam M, Anderson S A (2008). Fate mapping Nkx2.1-lineage cells in the mouse telencephalon. J Comp Neurol, 506(1): 16-29

DOI PMID

79
Xu T, Rubin G M (1993). Analysis of genetic mosaics in developing and adult Drosophila tissues. Development, 117(4): 1223-1237

PMID

80
Yang S B, Mclemore K D, Tasic B, Luo L, Jan Y N, Jan L Y (2012). Kv1.1-dependent control of hippocampal neuron number as revealed by mosaic analysis with double markers. J Physiol, 590(Pt 11): 2645-2658

PMID

81
Yingling J, Toyo-Oka K, Wynshaw-Boris A (2003). Miller-Dieker syndrome: analysis of a human contiguous gene syndrome in the mouse. Am J Hum Genet, 73(3): 475-488

DOI PMID

82
Yingling J, Youn Y H, Darling D, Toyo-Oka K, Pramparo T, Hirotsune S, Wynshaw-Boris A (2008). Neuroepithelial stem cell proliferation requires LIS1 for precise spindle orientation and symmetric division. Cell, 132(3): 474-486

DOI PMID

83
Youn Y H, Pramparo T, Hirotsune S, Wynshaw-Boris A (2009). Distinct dose-dependent cortical neuronal migration and neurite extension defects in Lis1 and Ndel1 mutant mice. J Neurosci, 29: 15520-15530

84
Young P, Qiu L, Wang D, Zhao S, Gross J, Feng G (2008). Single-neuron labeling with inducible Cre-mediated knockout in transgenic mice. Nat Neurosci, 11(6): 721-728

DOI PMID

85
Zhang F, Aravanis A M, Adamantidis A, de Lecea L, Deisseroth K (2007). Circuit-breakers: optical technologies for probing neural signals and systems. Nat Rev Neurosci, 8(8): 577-581

DOI PMID

86
Zhu X, Bergles D E, Nishiyama A (2008). NG2 cells generate both oligodendrocytes and gray matter astrocytes. Development, 135(1): 145-157

DOI PMID

87
Zhuo L, Theis M, Alvarez-Maya I, Brenner M, Willecke K, Messing A (2001). hGFAP-cre transgenic mice for manipulation of glial and neuronal function in vivo. Genesis, 31(2): 85-94

DOI PMID

88
Zong H, Espinosa J S, Su H H, Muzumdar M D, Luo L (2005). Mosaic analysis with double markers in mice. Cell, 121(3): 479-492

DOI PMID

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