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Hox genes and the molecular bases of vertebrate development

English title Hox genes and the molecular bases of vertebrate development
Applicant Duboule Denis
Number 122008
Funding scheme Project funding (Div. I-III)
Research institution Département de Génétique et Evolution Faculté des Sciences Université de Genève
Institution of higher education University of Geneva - GE
Main discipline Embryology, Developmental Biology
Start/End 01.10.2008 - 30.09.2011
Approved amount 930'000.00
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Keywords (14)

Morphogenesis; transcription factors; development; pattern formation; evolution; gene regulation; ChIP on Chip; recombination; embryos; regulation; Hox genes; mouse; transgenesis; genetics

Lay Summary (English)

Lead
Lay summary
We are interested in the regulatory mechanisms underlying vertebrate pattern formation, in both developmental and evolutionary contexts. We would like to understand how animals develop, including humans, and how the diversity of vertebrates evolved from ancestral animals. For the past 20 years, we have largely focused on the family of Hox genes, commonly referred to as 'architect genes', which are responsible for the general organization of the body structures. As an experimental system we used the house mouse, which can be genetically modified via technologies developed in the laboratory involving the simple crossing of animals (TAMERE and STRING), combined with biochemical and genomic analyses. We also hope that the understanding of mammalian development, at the molecular level, will help understanding the molecular aetiology of some genetic syndromes and diseases.
Direct link to Lay Summary Last update: 21.02.2013

Responsible applicant and co-applicants

Employees

Publications

Publication
Analysis of the dynamics of limb transcriptomes during mouse development.
Gyurján Istvan, Sonderegger Bernhard, Naef Felix, Duboule Denis (2011), Analysis of the dynamics of limb transcriptomes during mouse development., in BMC developmental biology, 11.
A genetic approach to the transcriptional regulation of hox gene clusters.
Tschopp Patrick, Duboule Denis (2011), A genetic approach to the transcriptional regulation of hox gene clusters., in Annual review of genetics, 45, 145-66.
A regulatory archipelago controls hox genes transcription in digits.
Montavon Thomas, Soshnikova Natalia, Mascrez Bénédicte, Joye Elisabeth, Thevenet Laurie, Splinter Erik, de Laat Wouter, Spitz François, Duboule Denis (2011), A regulatory archipelago controls hox genes transcription in digits., in Cell, 147(5), 1132-45.
The dynamic architecture of Hox gene clusters.
Noordermeer Daan, Leleu Marion, Splinter Erik, Rougemont Jacques, De Laat Wouter, Duboule Denis (2011), The dynamic architecture of Hox gene clusters., in Science (New York, N.Y.), 334(6053), 222-5.
Reshuffling genomic landscapes to study the regulatory evolution of Hox gene clusters.
Tschopp Patrick, Fraudeau Nadine, Béna Frédérique, Duboule Denis (2011), Reshuffling genomic landscapes to study the regulatory evolution of Hox gene clusters., in Proceedings of the National Academy of Sciences of the United States of America, 108(26), 10632-7.
Structural and functional differences in the long non-coding RNA hotair in mouse and human.
Schorderet Patrick, Duboule Denis (2011), Structural and functional differences in the long non-coding RNA hotair in mouse and human., in PLoS genetics, 7(5).
A regulatory 'landscape effect' over the HoxD cluster.
Tschopp Patrick, Duboule Denis (2011), A regulatory 'landscape effect' over the HoxD cluster., in Developmental biology, 351(2), 288-96.
A systematic enhancer screen using lentivector transgenesis identifies conserved and non-conserved functional elements at the Olig1 and Olig2 locus.
Friedli Marc, Barde Isabelle, Arcangeli Mélanie, Verp Sonia, Quazzola Alexandra, Zakany Jozsef, Lin-Marq Nathalie, Robyr Daniel, Attanasio Catia, Spitz François, Duboule Denis, Trono Didier, Antonarakis Stylianos E (2010), A systematic enhancer screen using lentivector transgenesis identifies conserved and non-conserved functional elements at the Olig1 and Olig2 locus., in PloS one, 5(12).
Functional analysis of CTCF during mammalian limb development.
Soshnikova Natalia, Montavon Thomas, Leleu Marion, Galjart Niels, Duboule Denis (2010), Functional analysis of CTCF during mammalian limb development., in Developmental cell, 19(6), 819-30.
The evo-devo comet.
Duboule Denis (2010), The evo-devo comet., in EMBO reports, 11(7).
Homeobox genes d11-d13 and a13 control mouse autopod cortical bone and joint formation.
Villavicencio-Lorini Pablo, Kuss Pia, Friedrich Julia, Haupt Julia, Farooq Muhammed, Türkmen Seval, Duboule Denis, Hecht Jochen, Mundlos Stefan (2010), Homeobox genes d11-d13 and a13 control mouse autopod cortical bone and joint formation., in The Journal of clinical investigation, 120(6), 1994-2004.
Additive and global functions of HoxA cluster genes in mesoderm derivatives.
Di-Poï Nicolas, Koch Ute, Radtke Freddy, Duboule Denis (2010), Additive and global functions of HoxA cluster genes in mesoderm derivatives., in Developmental biology, 341(2), 488-98.
The origin of digits: expression patterns versus regulatory mechanisms.
Woltering Joost M, Duboule Denis (2010), The origin of digits: expression patterns versus regulatory mechanisms., in Developmental cell, 18(4), 526-32.
Changes in Hox genes' structure and function during the evolution of the squamate body plan.
Di-Poï Nicolas, Montoya-Burgos Juan I, Miller Hilary, Pourquié Olivier, Milinkovitch Michel C, Duboule Denis (2010), Changes in Hox genes' structure and function during the evolution of the squamate body plan., in Nature, 464(7285), 99-103.
Conserved elements within open reading frames of mammalian Hox genes.
Woltering Joost M, Duboule Denis (2009), Conserved elements within open reading frames of mammalian Hox genes., in Journal of biology, 8(2).
The Hox complex - an interview with Denis Duboule. Interviewed by Richardson, Michael K.
Duboule Denis (2009), The Hox complex - an interview with Denis Duboule. Interviewed by Richardson, Michael K., in The International journal of developmental biology, 53(5-6), 717-23.
Epigenetic regulation of vertebrate Hox genes: a dynamic equilibrium.
Soshnikova Natalia, Duboule Denis (2009), Epigenetic regulation of vertebrate Hox genes: a dynamic equilibrium., in Epigenetics : official journal of the DNA Methylation Society, 4(8), 537-40.
Epigenetic temporal control of mouse Hox genes in vivo.
Soshnikova Natalia, Duboule Denis (2009), Epigenetic temporal control of mouse Hox genes in vivo., in Science (New York, N.Y.), 324(5932), 1320-3.
Atypical relaxation of structural constraints in Hox gene clusters of the green anole lizard.
Di-Poï Nicolas, Montoya-Burgos Juan I, Duboule Denis (2009), Atypical relaxation of structural constraints in Hox gene clusters of the green anole lizard., in Genome research, 19(4), 602-10.
Uncoupling time and space in the collinear regulation of Hox genes.
Tschopp Patrick, Tarchini Basile, Spitz François, Zakany Jozsef, Duboule Denis (2009), Uncoupling time and space in the collinear regulation of Hox genes., in PLoS genetics, 5(3).
Rostral and caudal pharyngeal arches share a common neural crest ground pattern.
Minoux Maryline, Antonarakis Gregory S, Kmita Marie, Duboule Denis, Rijli Filippo M (2009), Rostral and caudal pharyngeal arches share a common neural crest ground pattern., in Development (Cambridge, England), 136(4), 637-45.

Awards

Title Year
Prix de la Fondation pour Genève 2011
Dr. honoris causa from the Ecole Normale Supérieure, Paris 2010
INSERM International Prize 2010
European SpineWeek medal 2008

Associated projects

Number Title Start Funding scheme
155863 Collinear regulation of HoxD genes during development and evolution 01.11.2014 Project funding (Div. I-III)
138662 Hox genes and the molecular bases of vertebrate development 01.11.2011 Project funding (Div. I-III)
102277 Hox genes and the molecular basis of vertebrate development 01.10.2003 Project funding (Div. I-III)

Abstract

We are interested in the regulatory mechanisms underlying vertebrate pattern formation, in both developmental and evolutionary contexts. For the past 20 years, we have largely focused on Hox genes, a family of transcription factors that display special paradigmatic values, regarding their regulatory strategies, their functional organization and their key roles in morphological evolution. In the course of our last two FNRS grants, we initiated an ambitious program aimed at genetically dissecting these various aspects of Hox gene biology, either using the potential of established mouse genetic manipulations, or by designing and implementing powerful strategies relying upon inter-chromosomal or large-scale genomic recombinations (TAMERE and STRING). This grant proposal is mostly concerned with the last phase of this programme, i.e. the production of a few last genetic configurations and the use of biochemical approaches available in the laboratory (ChIP on chip, 3C and 4C) to capitalize on this material by addressing the question of global gene regulation at this particular locus, as a potential paradigm for genome-wide studies. The combination of these cutting edge technological approaches with our large collection of mouse stocks should provide a unique opportunity to solve questions regarding the relationships between genome structure and regulation, which have become increasingly important over the past few years.While a major effort will be concentrated on the regulation of Hox gene regulation, the past four years of work have allowed us to produce the tools necessary to also evaluate the function of these genes in a variety of developmental and evolutionary contexts. A) Regulation of Hox gene expression1)We will continue our efforts to understand the mechanistic bases of collinearities, i.e. those mechanisms by which neighboring Hox genes are activated one after the other in overlapping anterior to posterior domains, in the trunk as well as in the proximal limbs. The nature of these processes, one of which has been solved during the last granting period (in developing digits), represents one of the key challenges for my laboratory. While we now have in our hands most of the necessary tools (stocks of mice and analytical approaches) to bring an answer to this question, during the development of the major body axis, some large inversions and deletions still remain to be produced at this locus, such as to fully understand the regulations at work.2)We will use a comprehensive approach to study those global regulatory controls, which have evolved along with a variety of structures such as the digits, the external genitalia, the intestinal caecum, the whisker pads or the emerging somites. These enhancer elements are of critical mechanistic and evolutionary importance and will be looked for by using both a genetic approach in vivo, a large-scale transgenic program using a lentivirus-based system and biochemical analyses carried out on a two megabase large DNA landscape on tiling arrays. B) Function of Hox genesWe shall continue our studies of Hox gene functions by using the allelic series we have constructed over the past years. This mostly involves multiple gene (cluster) deletions, conditional gene inactivations using the cre/loxP system and targeted gain of functions. We will focus this work on a few novel directions, not yet investigated in great deepth in the field of Hox genes, in particular regarding gain of function effects upon the developing nervous system and the early stages of mesoderm formation, as well as multiple cluster deletions, an approach unique to my laboratory due to the logistic problems it represents (duration and number of breeding animals).C) Evolutionnary aspectsA small unit of the laboratory will continue to implement a few targeted evo-devo projects, continuing in the same thematic, i.e. the importance of Hox gene regulation during morphological evolution, in particular of paired appendages. Two projects are concerned with the necessary annotation and characterisation of squamates Hox clusters (lizards and snakes), whereas the third one is to help understand the regulatory bases of the extraordinary flexibility in the morphological evolution of teleostei fishes, as viewed from the perspective of Hox clusters. Besides their intrinsic interests, these projects are of great importance to maintain the laboratory in a multidisciplinary context, such as to both keep our visibility in these fields and offer the widest possible formation to our students and postdocs.
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