A resource of vectors and ES cells for targeted deletion of microRNAs in mice

Prosser, Haydn M.; Koike-Yusa, Hiroko; Cooper, James D.; Law, Frances; Bradley, Allan

doi:10.1038/nbt.1929

Cited by 90 publications

(79 citation statements)

References 40 publications

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“…The Six2-Cre-mediated knockout of Dicer1 (Nagalakshmi et al 2011) has already demonstrated the importance of miRNAs in these cells, and specific miRNAs found deregulated in Wilms' tumors would be strong candidates to analyze for their roles in nephron progenitors. A mouse ESC resource for the generation of miRNA reporter and conditional knockout alleles has been described (Prosser et al 2011), and, combined with Cre drivers active in many different cell types in the developing kidney, this would provide the experimental platform to analyze this in more detail.…”

Section: Discussionmentioning

confidence: 99%

The yin and yang of kidney development and Wilms’ tumors

2015

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Wilms’ tumor, or nephroblastoma, is the most common pediatric renal cancer. The tumors morphologically resemble embryonic kidneys with a disrupted architecture and are associated with undifferentiated metanephric precursors. Here, we discuss genetic and epigenetic findings in Wilms’ tumor in the context of renal development. Many of the genes implicated in Wilms’ tumorigenesis are involved in the control of nephron progenitors or the microRNA (miRNA) processing pathway. Whereas the first group of genes has been extensively studied in normal development, the second finding suggests important roles for miRNAs in general—and specific miRNAs in particular—in normal kidney development that still await further analysis. The recent identification of Wilms’ tumor cancer stem cells could provide a framework to integrate these pathways and translate them into new or improved therapeutic interventions.

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Section: Discussionmentioning

confidence: 99%

The yin and yang of kidney development and Wilms’ tumors

2015

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“…Previously targeted ES cells at each of the three miR-196 loci have been generated (74). Correctly targeted JM8A3 ES cells were reconfirmed by Southern blot and used to generate germ-line transmitting KO lines.…”

Section: Mir-196a1mentioning

confidence: 99%

Independent regulation of vertebral number and vertebral identity by microRNA-196 paralogs

Wong

Agarwal

Mansfield

et al. 2015

Proc. Natl. Acad. Sci. U.S.A.

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The Hox genes play a central role in patterning the embryonic anterior-to-posterior axis. An important function of Hox activity in vertebrates is the specification of different vertebral morphologies, with an additional role in axis elongation emerging. The miR-196 family of microRNAs (miRNAs) are predicted to extensively target Hox 3′ UTRs, although the full extent to which miR-196 regulates Hox expression dynamics and influences mammalian development remains to be elucidated. Here we used an extensive allelic series of mouse knockouts to show that the miR-196 family of miRNAs is essential both for properly patterning vertebral identity at different axial levels and for modulating the total number of vertebrae. All three miR-196 paralogs, 196a1, 196a2, and 196b, act redundantly to pattern the midthoracic region, whereas 196a2 and 196b have an additive role in controlling the number of rib-bearing vertebra and positioning of the sacrum. Independent of this, 196a1, 196a2, and 196b act redundantly to constrain total vertebral number. Loss of miR-196 leads to a collective up-regulation of numerous trunk Hox target genes with a concomitant delay in activation of caudal Hox genes, which are proposed to signal the end of axis extension. Additionally, we identified altered molecular signatures associated with the Wnt, Fgf, and Notch/segmentation pathways and demonstrate that miR-196 has the potential to regulate Wnt activity by multiple mechanisms. By feeding into, and thereby integrating, multiple genetic networks controlling vertebral number and identity, miR-196 is a critical player defining axial formulae.

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“…Recent progress includes resources for miRNA overexpression in Drosophila, which cover 165 miRNAs (Bejarano et al, 2012;Schertel et al, 2012;Szuplewski et al, 2012). Collections of targeted knockout ES cells will facilitate production of miRNA mutant mice (Park et al, 2012;Prosser et al, 2011).…”

Section: Introductionmentioning

confidence: 99%

Systematic Study of Drosophila MicroRNA Functions Using a Collection of Targeted Knockout Mutations

et al. 2014

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MicroRNAs are abundant in animal genomes, yet little is known about their functions in vivo. Here, we report the production of 80 new Drosophila miRNA mutants by targeted homologous recombination. These mutants remove 104 miRNAs. Together with 15 previously reported mutants, this collection includes 95 mutants deleting 130 miRNAs. Collectively, these genes produce over 99% of all Drosophila miRNAs, measured by miRNA sequence reads. We present a survey of developmental and adult miRNA phenotypes. Over 80% of the mutants showed at least one phenotype using a p < 0.01 significance threshold. We observed a significant correlation between miRNA abundance and phenotypes related to survival and lifespan, but not to most other phenotypes. miRNA cluster mutants were no more likely than single miRNA mutants to produce significant phenotypes. This mutant collection will provide a resource for future analysis of the biological roles of Drosophila miRNAs.

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A resource of vectors and ES cells for targeted deletion of microRNAs in mice

Cited by 90 publications

References 40 publications

The yin and yang of kidney development and Wilms’ tumors

The yin and yang of kidney development and Wilms’ tumors

Independent regulation of vertebral number and vertebral identity by microRNA-196 paralogs

Systematic Study of Drosophila MicroRNA Functions Using a Collection of Targeted Knockout Mutations

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