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MASTR: a technique for mosaic mutant analysis with spatial and temporal control of recombination using conditional floxed alleles in mice.

ABSTRACT: Mosaic mutant analysis, the study of cellular defects in scattered mutant cells in a wild-type environment, is a powerful approach for identifying critical functions of genes and has been applied extensively to invertebrate model organisms. A highly versatile technique has been developed in mouse: MASTR (mosaic mutant analysis with spatial and temporal control of recombination), which utilizes the increasing number of floxed alleles and simultaneously combines conditional gene mutagenesis and cell marking for fate analysis. A targeted allele (R26(MASTR)) was engineered; the allele expresses a GFPcre fusion protein following FLP-mediated recombination, which serves the dual function of deleting floxed alleles and marking mutant cells with GFP. Within 24 hr of tamoxifen administration to R26(MASTR) mice carrying an inducible FlpoER transgene and a floxed allele, nearly all GFP-expressing cells have a mutant allele. The fate of single cells lacking FGF8 or SHH signaling in the developing hindbrain was analyzed using MASTR, and it was revealed that there is only a short time window when neural progenitors require FGFR1 for viability and that granule cell precursors differentiate rapidly when SMO is lost. MASTR is a powerful tool that provides cell-type-specific (spatial) and temporal marking of mosaic mutant cells and is broadly applicable to developmental, cancer, and adult stem cell studies.

SUBMITTER: Lao Z

PROVIDER: S-EPMC3460375 | biostudies-literature | 2012 Aug

REPOSITORIES: biostudies-literature

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MASTR: a technique for mosaic mutant analysis with spatial and temporal control of recombination using conditional floxed alleles in mice.

Lao Zhimin Z Raju G Praveen GP Bai C Brian CB Joyner Alexandra L AL

Cell reports 20120809 2

Mosaic mutant analysis, the study of cellular defects in scattered mutant cells in a wild-type environment, is a powerful approach for identifying critical functions of genes and has been applied extensively to invertebrate model organisms. A highly versatile technique has been developed in mouse: MASTR (mosaic mutant analysis with spatial and temporal control of recombination), which utilizes the increasing number of floxed alleles and simultaneously combines conditional gene mutagenesis and ce ...[more]

PMID: 22884371

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Project description:Understanding how environmental variability (or randomness) affects evolution is of fundamental importance for biology. The presence of temporal or spatial variability significantly affects the competition dynamics in populations, and gives rise to some counterintuitive observations. In this paper, we consider both birth-death (BD) or death-birth (DB) Moran processes, which are set up on a circular or a complete graph. We investigate spatial and temporal variability affecting division and/or death parameters. Assuming that mutant and wild-type fitness parameters are drawn from an identical distribution, we study mutant fixation probability and timing. We demonstrate that temporal and spatial types of variability possess fundamentally different properties. Under temporal randomness, in a completely mixed system, minority mutants experience (i) higher than neutral fixation probability and a higher mean conditional fixation time, if the division rates are affected by randomness and (ii) lower fixation probability and lower mean conditional fixation time if the death rates are affected. Once spatial restrictions are imposed, however, these effects completely disappear, and mutants in a circular graph experience neutral dynamics, but only for the DB update rule in case (i) and for the BD rule in case (ii) above. In contrast to this, in the case of spatially variable environment, both for BD/DB processes, both for complete/circular graph and both for division/death rates affected, minority mutants experience a higher than neutral probability of fixation. Fixation time, however, is increased by randomness on a circle, while it decreases for complete graphs under random division rates. A basic difference between temporal and spatial kinds of variability is the types of correlations that occur in the system. Under temporal randomness, mutants are spatially correlated with each other (they simply have equal fitness values at a given moment of time; the same holds for wild-types). Under spatial randomness, there are subtler, temporal correlations among mutant and wild-type cells, which manifest themselves by cells of each type 'claiming' better spots for themselves. Applications of this theory include cancer generation and biofilm dynamics.

Dataset Information

MASTR: a technique for mosaic mutant analysis with spatial and temporal control of recombination using conditional floxed alleles in mice.

Publications

MASTR: a technique for mosaic mutant analysis with spatial and temporal control of recombination using conditional floxed alleles in mice.

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