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Transgenic rescue of the mouse t complex haplolethal locus Thl1

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Abstract

Chromosomal deletions can uncover haploinsufficient or imprinted regions of the genome. Previously, the haploinsufficient locus t haplolethal 1 (Thl1) was identified and localized to a 1.3-Mb region using overlapping deletions around the Sod2 and D17Leh94 loci of the mouse t complex on Chr 17. Germline chimeric mice, produced from embryonic stem (ES) cells containing radiation-induced deletions of the Thl1 locus, never produced viable deletion-bearing progeny when mated to C57BL/6J (B6) females. However, deletion-bearing offspring could be obtained by mating to females of other strains. In this article we describe a transgenic approach to narrow the critical region for Thl1. BAC clones were introduced into a deletion-bearing ES cell line and one was shown to rescue the Thl1 phenotype, reducing the critical region to 140 kb. Analysis of the gene content of this region suggests two strong Thl1 candidates, Pdcd2 and a novel SET domain-containing gene termed Tset1. A more detailed analysis using mice carrying overlapping deletions identified subregions that influence the phenotypic characteristics of Thl1 hemizygotes.

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References

  • Adams DJ, Biggs PJ, Cox T, Davies R, van der Weyden L, et al. (2004) Mutagenic insertion and chromosome engineering resource (MICER). Nat Genet 36: 867-871

    Article  PubMed  CAS  Google Scholar 

  • Agresti A (1996) An introduction to categorical data analysis. (New York: Wiley)

    Google Scholar 

  • Altschul SF, Gish W, Miller W, Myers EW, Lipman DJ (1990) Basic local alignment search tool. J Mol Biol 215: 403-410

    Article  PubMed  CAS  Google Scholar 

  • Bauchwitz R, Constantini F (1998) YAC transgenesis: a study of conditions to protect YAC DNA from breakage and a protocol for transfection. Biochim Biophys Acta 1401: 21-37

    PubMed  CAS  Google Scholar 

  • Bergstrom DE, Bergstrom RA, Munroe RJ, Lee BK, Browning VL, et al. (2003) Overlapping deletions spanning the proximal two-thirds of the mouse t complex. Mamm Genome 14: 817-829

    Article  PubMed  CAS  Google Scholar 

  • Brewer C, Holloway S, Zawalnyski P, Schinzel A, FitzPatrick D (1998) A chromosomal deletion map of human malformations. Am J Hum Genet 63: 1153-1159

    Article  PubMed  CAS  Google Scholar 

  • Brewer C, Holloway S, Zawalnyski P, Schinzel A, FitzPatrick D (1999) A chromosomal duplication map of malformations: regions of suspected haplo- and triplolethality–and tolerance of segmental aneuploidy—in humans. Am J Hum Genet 64: 1702-1708

    Article  PubMed  CAS  Google Scholar 

  • Browning VL, Bergstrom RA, Daigle S, Schimenti JC (2002) A haplolethal locus uncovered by deletions in the mouse T complex. Genetics 160: 675-682

    PubMed  CAS  Google Scholar 

  • Carmeliet P, Ferreira V, Breier G, Pollefeyt S, Kieckens L, et al. (1996) Abnormal blood vessel development and lethality in embryos lacking a single VEGF allele. Nature 380: 435-439

    Article  PubMed  CAS  Google Scholar 

  • Cui X, De Vivo I, Slany R, Miyamoto A, Firestein R, et al. (1998) Association of SET domain and myotubularin-related proteins modulates growth control. Nat Genet 18: 331-337

    Article  PubMed  CAS  Google Scholar 

  • Dixon J, Brakebusch C, Fassler R, Dixon MJ (2000) Increased levels of apoptosis in the prefusion neural folds underlie the craniofacial disorder, Treacher Collins syndrome. Hum Mol Genet 9: 1473-1480

    PubMed  CAS  Google Scholar 

  • Duarte A, Hirashima M, Benedito R, Trindade A, Diniz P, et al. (2004) Dosage-sensitive requirement for mouse Dll4 in artery development. Genes Dev 18: 2474-2478

    Article  PubMed  CAS  Google Scholar 

  • Ferrara N, Carver-Moore K, Chen H, Dowd M, Lu L, et al. (1996) Heterozygous embryonic lethality induced by targeted inactivation of the VEGF gene. Nature 380 : 439-442

    Article  PubMed  CAS  Google Scholar 

  • Gale NW, Dominguez MG, Noguera I, Pan L, Hughes V, et al. (2004) Haploinsufficiency of delta-like 4 ligand results in embryonic lethality due to major defects in arterial and vascular development. Proc Natl Acad Sci U S A 101: 15949-15954

    Article  PubMed  CAS  Google Scholar 

  • Goodwin NC, Ishida Y, Hartford S, Wnek C, Bergstrom RA, et al. (2001) DelBank: a mouse ES-cell resource for generating deletions. Nat Genet 28: 310-311

    Article  PubMed  CAS  Google Scholar 

  • Goto H, Motomura S, Wilson AC, Freiman RN, Nakabeppu Y, et al. (1997) A single-point mutation in HCF causes temperature-sensitive cell-cycle arrest and disrupts VP16 function. Genes Dev 11: 726-737

    PubMed  CAS  Google Scholar 

  • Krebs LT, Shutter JR, Tanigaki K, Honjo T, Stark KL et al. (2004) Haploinsufficient lethality and formation of arteriovenous malformations in Notch pathway mutants. Genes Dev 18: 2469-2473

    Article  PubMed  CAS  Google Scholar 

  • Lambertsson A (1998) The minute genes in Drosophila and their molecular functions. Adv Genet 38: 69-134

    PubMed  CAS  Google Scholar 

  • Lindsay EA, Botta A, Jurecic V, Carattini-Rivera S, Cheah Y-C, et al. (1999). Congenital heart disease in mice deficient for the DiGeorge syndrome region. Nature 401: 379-383

    Article  PubMed  CAS  Google Scholar 

  • Martianov I, Viville S, Davidson I (2002) RNA polymerase II transcription in murine cells lacking the TATA binding protein. Science 298: 1036-1039

    Article  PubMed  CAS  Google Scholar 

  • Milne TA, Briggs SD, Brock HW, Martin ME, Gibbs D, et al. (2002) MLL targets SET domain methyltransferase activity to Hox gene promoters. Mol Cell 10: 1107-1117

    Article  PubMed  CAS  Google Scholar 

  • Naf D, Wilson LA, Bergstrom RA, Smith RS, Goodwin NC, et al. (2001) Mouse models for the Wolf-Hirschhorn deletion syndrome. Hum Mol Genet 10: 91-98

    Article  PubMed  CAS  Google Scholar 

  • Prado A, Canal I, Ferrus A (1999) The haplolethal region at the 16F gene cluster of Drosophila melanogaster: structure and function. Genetics 151: 163-175

    PubMed  CAS  Google Scholar 

  • Ramirez-Solis R, Liu P, Bradley A (1995) Chromosome engineering in mice. Nature 378: 720-724

    Article  PubMed  CAS  Google Scholar 

  • Rauch A, Schellmoser S, Kraus C, Dorr HG, Trautmann U, et al. (2001) First known microdeletion within the Wolf-Hirschhorn syndrome critical region refines genotype-phenotype correlation. Am J Med Genet 99: 338-342

    Article  PubMed  CAS  Google Scholar 

  • Rozen S, Skaletsky H (2000) Primer3 on the WWW for general users and for biologist programmers. Methods Mol Biol 132: 365-386

    PubMed  CAS  Google Scholar 

  • Schultz J (1929) The Minute reaction in the development of Drosophila melanogaster. Genetics 14: 366-419

    PubMed  CAS  Google Scholar 

  • Silver LM (1993) The peculiar journey of a selfish chromosome: mouse t haplotypes and meiotic drive. Trends Genet 9: 250-254

    Article  PubMed  CAS  Google Scholar 

  • Stassen MJ, Bailey D, Nelson S, Chinwalla V, Harte PJ (1995) The Drosophila trithorax proteins contain a novel variant of the nuclear receptor type DNA binding domain and an ancient conserved motif found in other chromosomal proteins. Mech Dev 52: 209-223

    Article  PubMed  CAS  Google Scholar 

  • Trinh P, McLysaght A, Sankoff D (2004) Genomic features in the breakpoint regions between syntenic blocks. Bioinformatics 20: i318-i325

    Article  PubMed  CAS  Google Scholar 

  • Tschiersch B, Hofmann A, Krauss V, Dorn R, Korge G, et al. (1994) The protein encoded by the Drosophila position-effect variegation suppressor gene Su(var)3-9 combines domains of antagonistic regulators of homeotic gene complexes. EMBO J 13: 3822-3831

    PubMed  CAS  Google Scholar 

  • Vaux DL, Hacker G (1995) Cloning of mouse RP-8 cDNA and its expression during apoptosis of lymphoid and myeloid cells. DNA Cell Biol 14: 189-193

    Article  PubMed  CAS  Google Scholar 

  • Walz K, Caratini-Rivera S, Bi W, Fonseca P, Mansouri DL, et al. (2003) Modeling del(17)(p11.2p11.2) and dup(17)(p11.2p11.2) contiguous gene syndromes by chromosome engineering in mice: phenotypic consequences of gene dosage imbalance. Mol Cell Biol 23: 3646-3655

    Article  PubMed  CAS  Google Scholar 

  • Wang Z, Engler P, Longacre A, Storb U (2001) An efficient method for high-fidelity BAC/PAC retrofitting with a selectable marker for mammalian cell transfection. Genome Res 11: 137-142

    Article  PubMed  CAS  Google Scholar 

  • Wright TJ, Ricke DO, Denison K, Abmayr S, Cotter PD, et al. (1997) A transcript map of the newly defined 165 kb Wolf-Hirschhorn syndrome critical region. Hum Mol Genet 6: 317-324

    Article  PubMed  CAS  Google Scholar 

  • 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: 475-488

    Article  PubMed  CAS  Google Scholar 

  • You Y, Bergstrom R, Klemm M, Lederman B, Nelson H, et al. (1997) Chromosomal deletion complexes in mice by radiation of embryonic stem cells. Nat Genet 15: 285-288

    Article  PubMed  CAS  Google Scholar 

  • Zollino M, Lecce R, Fischetto R, Murdolo M, Faravelli F, et al. (2003) Mapping the Wolf-Hirschhorn syndrome phenotype outside the currently accepted WHS critical region and defining a new critical region, WHSCR-2. Am J Hum Genet 72: 590-597

    Article  PubMed  CAS  Google Scholar 

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Acknowledgments

The authors thank Weidong Zhang and Benjamin King of the Computational Biology Resource at The Jackson Laboratory for statistical analysis, Jennifer Ashurst of the Wellcome Trust Sanger Institute for manual annotation, and David Bergstrom of The Jackson Laboratory and Alison Coffey of the Wellcome Trust Sanger Institute for advice and critical comments. This work was supported by an NIH grant (R01 HD24374) to JS.

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Author notes

  1. Gareth R. Howell

    Present address: Department of Molecular Biology and Biotechnology, The University of Sheffield, Firth Court, Western Bank, Sheffield, S10 2TN, UK

  2. Robert J. Munroe & John C. Schimenti

    Present address: Department of Biomedical Sciences, College of Veterinary Medicine, Cornell University, Ithaca, New York, 14853-6401, USA

Authors and Affiliations

  1. The Jackson Laboratory, 600 Main Street, Bar Harbor, Maine, 04660, USA

    Gareth R. Howell, Robert J. Munroe & John C. Schimenti

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  1. Gareth R. Howell
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Correspondence to John C. Schimenti.

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Howell, G.R., Munroe, R.J. & Schimenti, J.C. Transgenic rescue of the mouse t complex haplolethal locus Thl1 . Mamm Genome 16, 838–846 (2005). https://doi.org/10.1007/s00335-005-0045-8

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  • DOI: https://doi.org/10.1007/s00335-005-0045-8

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