Abstract
Following their duplications at the base of the vertebrate clade, Hox gene clusters underwent remarkable sub- and neo-functionalization events. Many of these evolutionary innovations can be associated with changes in the transcriptional regulation of their genes, where an intricate relationship between the structure of the gene cluster and the architecture of the surrounding genomic landscape is at play. Here, we report on a portfolio of in vivo genome engineering strategies in mice, which have been used to probe and decipher the genetic and molecular underpinnings of the complex regulatory mechanisms implemented at these loci.
Access this chapter
Tax calculation will be finalised at checkout
Purchases are for personal use only
References
Krumlauf R (1994) Hox genes in vertebrate development review. Cell 78:191–201
Deschamps J (2007) Ancestral and recently recruited global control of the Hox genes in development. Curr Opin Genet Dev 17:422–427. doi:10.1016/j.gde.2007.07.008
Ohno S (1970) Evolution by gene duplication. George Alien & Unwin Ltd., London
Garcia-Fernàndez J (2005) The genesis and evolution of homeobox gene clusters. Nat Publ Group 6:881–892. doi:10.1038/nrg1723
King MC, Wilson AC (1975) Evolution at two levels in humans and chimpanzees. Science 188:107–116
Duboule D (2007) The rise and fall of Hox gene clusters. Development 134:2549–2560. doi:10.1242/dev.001065
Brault V, Pereira P, Duchon A, Hérault Y (2006) Modeling chromosomes in mouse to explore the function of genes, genomic disorders, and chromosomal organization. PLoS Genet 2:e86
Hérault Y, Rassoulzadegan M, Cuzin F, Duboule D (1998) Engineering chromosomes in mice through targeted meiotic recombination (TAMERE). Nat Genet 20:381–384. doi:10.1038/3861
Spitz F, Herkenne C, Morris MA, Duboule D (2005) Inversion-induced disruption of the Hoxd cluster leads to the partition of regulatory landscapes. Nat Genet 37:889–893. doi:10.1038/ng1597
Tschopp P, Fraudeau N, Béna F, Duboule D (2011) Reshuffling genomic landscapes to study the regulatory evolution of Hox gene clusters. Proc Natl Acad Sci U S A 108:10632–10637. doi:10.1073/pnas.1102985108
Marinić M, Aktas T, Ruf S, Spitz F (2013) An integrated Holo-Enhancer unit defines tissue and gene specificity of the Fgf8 regulatory landscape. Dev Cell 24:530–542. doi:10.1016/j.devcel.2013.01.025
Tschopp P, Duboule D (2011) A genetic approach to the transcriptional regulation of Hox gene clusters. Annu Rev Genet 45:145–166. doi:10.1146/annurev-genet-102209-163429
Ruf S, Symmons O, Uslu VV et al (2011) Large-scale analysis of the regulatory architecture of the mouse genome with a transposon-associated sensor. Nat Genet 43:379–386. doi:10.1038/ng.790
Montavon T, Soshnikova N, Mascrez B et al (2011) A regulatory archipelago controls Hox genes transcription in digits. Cell 147:1132–1145. doi:10.1016/j.cell.2011.10.023
Montavon TT, Thevenet LL, Duboule DD (2012) Impact of copy number variations (CNVs) on long-range gene regulation at the HoxD locus. Proc Natl Acad Sci U S A 109:20204–20211. doi:10.1073/pnas.1217659109
Andrey G, Montavon T, Mascrez B et al (2013) A switch between topological domains underlies HoxD genes collinearity in mouse limbs. Science 340:1234167. doi:10.1126/science.1234167
Sauer B, Henderson N (1988) Site-specific DNA recombination in mammalian cells by the Cre recombinase of bacteriophage P1. Proc Natl Acad Sci U S A 85(14):5166–5170
Orban PC, Chui D, Marth JD (1992) Tissue-and site-specific DNA recombination in transgenic mice. Proc Natl Acad Sci U S A 89(15):6861–6865
Tarchini B, Nguyen Huynh TH, Duboule D (2005) HoxD cluster scanning deletions identify multiple defects leading to paralysis in the mouse mutant Ironside. Genes Dev 19:2862–2876. doi:10.1101/gad.351105
Tarchini B, Duboule D (2006) Control of Hoxd genes’ collinearity during early limb development. Dev Cell 10:93–103. doi:10.1016/j.devcel.2005.11.014
van der Hoeven F, Zakany J, Duboule D (1996) Gene transpositions in the HoxD complex reveal a hierarchy of regulatory controls. Cell 85:1025–1035
Spitz F, Gonzalez F, Peichel C et al (2001) Large scale transgenic and cluster deletion analysis of the HoxD complex separate an ancestral regulatory module from evolutionary innovations. Genes Dev 15:2209–2214. doi:10.1101/gad.205701
Tschopp P, Christen AJ, Duboule D (2012) Bimodal control of Hoxd gene transcription in the spinal cord defines two regulatory subclusters. Development 139:929–939. doi:10.1242/dev.076794
Skarnes WC, von Melchner H, Wurst W et al (2004) A public gene trap resource for mouse functional genomics. Nat Genet 36:543–544. doi:10.1038/ng0604-543
Wu S, Ying G, Wu Q, Capecchi MR (2007) Toward simpler and faster genome-wide mutagenesis in mice. Nat Genet 39:922–930. doi:10.1038/ng2060
Vidal F, Sage J, Cuzin F, Rassoulzadegan M (1998) Cre expression in primary spermatocytes: a tool for genetic engineering of the germ line. Mol Reprod Dev 51:274–280. doi:10.1002/(SICI)1098-2795(199811)51:3<274::AID-MRD6>3.0.CO;2-M
Tang S-HE, Silva FJ, Tsark WMK, Mann JR (2002) A Cre/loxP-deleter transgenic line in mouse strain 129S1/SvImJ. Genesis 32:199–202. doi:10.1002/gene.10030
Gough SM, Slape CI, Aplan PD (2011) NUP98 gene fusions and hematopoietic malignancies: common themes and new biologic insights. Blood 118:6247–6257. doi:10.1182/blood-2011-07-328880
Dymecki SM (1996) Flp recombinase promotes site-specific DNA recombination in embryonic stem cells and transgenic mice. Proc Natl Acad Sci U S A 93:6191–6196
Zakany JJ, Kmita MM, Alarcon PP et al (2001) Localized and transient transcription of Hox genes suggests a link between patterning and the segmentation clock. Cell 106:207–217. doi:10.1016/S0092-8674(01)00436-6
Godwin AR, Stadler HS, Nakamura K, Capecchi MR (1998) Detection of targeted GFP-Hox gene fusions during mouse embryogenesis. Proc Natl Acad Sci U S A 95:13042–13047
Hérault Y, Kmita M, Sawaya CC, Duboule D (2002) A nested deletion approach to generate Cre deleter mice with progressive Hox profiles. Int J Dev Biol 46:185–191
Dixon JR, Selvaraj S, Yue F et al (2013) Topological domains in mammalian genomes identified by analysis of chromatin interactions. Nature 485:376–380. doi:10.1038/nature11082
Noordermeer DD, Leleu MM, Splinter EE et al (2011) The dynamic architecture of Hox gene clusters. Science 334:222–225. doi:10.1126/science.1207194
Soshnikova N, Duboule D (2009) Epigenetic temporal control of mouse Hox genes in vivo. Science 324:1320–1323. doi:10.1126/science.1171468
Grégoire D, Kmita M (2008) Recombination between inverted loxP sites is cytotoxic for proliferating cells and provides a simple tool for conditional cell ablation. Proc Natl Acad Sci U S A 105:14492–14496
Tschopp P, Duboule D (2011) A regulatory “landscape effect” over the HoxD cluster. Dev Biol 351:288–296. doi:10.1016/j.ydbio.2010.12.034
Acknowledgements
Patrick Tschopp is supported by postdoctoral fellowships from the Swiss National Science Foundation (SNF), EMBO, and the Human Frontiers Science Program (HFSP). Work in the Duboule laboratories is supported by the Ecole Polytechnique Fédérale de Lausanne, the University of Geneva, the National Center for Competence in Research Frontiers in Genetics, the Swiss National Research Fund, and the ERC grant SystemsHox.ch. We thank Bénédicte Mascrez for the organization of the genotyping pipeline and the supervision of mouse strain production.
Author information
Authors and Affiliations
Corresponding author
Editor information
Editors and Affiliations
Rights and permissions
Copyright information
© 2014 Springer Science+Business Media New York
About this protocol
Cite this protocol
Tschopp, P., Duboule, D. (2014). The Genetics of Murine Hox Loci: TAMERE, STRING, and PANTHERE to Engineer Chromosome Variants. In: Graba, Y., Rezsohazy, R. (eds) Hox Genes. Methods in Molecular Biology, vol 1196. Humana Press, New York, NY. https://doi.org/10.1007/978-1-4939-1242-1_6
Download citation
DOI: https://doi.org/10.1007/978-1-4939-1242-1_6
Published:
Publisher Name: Humana Press, New York, NY
Print ISBN: 978-1-4939-1241-4
Online ISBN: 978-1-4939-1242-1
eBook Packages: Springer Protocols