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Denis Duboule

Publications and source records attributed to Denis Duboule.

11 recordsLinked to original sources
PubMed2003

Organizing axes in time and space; 25 years of colinear tinkering.

During vertebrate development, clustered genes from the Hox family of transcription factors are activated in a precise temporal and spatial sequence that follows their chromosomal order (the "Hox clock"). Recent advances in the knowledge of the underlying mechanisms reveal that the embryo uses a variety of strategies to implement this colinear process, depending on both the type and the evolutionary history of axial structures. The search for a universal mechanism has likely hampered our understanding of this enigmatic phenomenon, which may be caused by various and unrelated regulatory processes, as long as the final distribution of proteins (the HOX code) is preserved.

Animals↗
PubMed2003

A global control region defines a chromosomal regulatory landscape containing the HoxD cluster.

During limb development, coordinated expression of several Hoxd genes is required in presumptive digits. We searched for the underlying control sequences upstream from the cluster and found Lunapark (Lnp), a gene which shares limb and CNS expression specificities with both Hoxd genes and Evx2, another gene located nearby. We used a targeted enhancer-trap approach to identify a DNA segment capable of directing reporter gene expression in both digits and CNS, following Lnp, Evx2, and Hoxd-specific patterns. This DNA region showed an unusual interspecies conservation, including with its pufferfish counterpart. It contains a cluster of global enhancers capable of controlling transcription of several genes unrelated in structure or function, thus defining large regulatory domains. These domains were interrupted in the Ulnaless mutation, a balanced inversion that modified the topography of the locus. We discuss the heuristic value of these results in term of locus specific versus gene-specific regulation.

5' Flanking Region↗
PubMed2003

An enhancer-titration effect induces digit-specific regulatory alleles of the HoxD cluster.

Mice carrying transgenes targeted upstream the HoxD cluster display abnormal digits, with alterations resembling those obtained with loss of functions of Hoxd genes. Because the HoxD cluster remained entirely untouched by the insertional events, we investigated whether these phenotypes were induced by regulatory modifications at a distance. We report here that these targeted relocations behaved as hypomorphic alleles of the distantly located gene Hoxd13 and showed that posterior Hoxd genes located in cis with the integration site were down-regulated. Genetic analyses suggested that this down-regulation resulted from the titration of the activity of a remote located enhancer sequence. These results indicate that the transcriptional efficiency of Hoxd genes in digits could be modulated by the presence of other, unrelated, promoters, within the regulatory landscape of this enhancer. Modifications in these latter transcription units may thus impact upon digit morphology, through misregulation of Hoxd genes, thus illustrating the "buffering effect" that such a global regulatory element can exert upon a short genomic interval.

Animals↗
PubMed2002

Serial deletions and duplications suggest a mechanism for the collinearity of Hoxd genes in limbs.

Hox genes, located at one end of the HoxD cluster, are essential for the development of the extremities of our limbs; that is, the digits. This 'collinear' correspondence is accompanied by a gradual decrease in the transcriptional efficiency of the genes. To decipher the underlying regulatory mechanisms, and thus to understand better how digits develop, we engineered a series of deletions and duplications in vivo. We find that HoxD genes compete for a remote enhancer that recognizes the locus in a polar fashion, with a preference for the 5' extremity. Modifications in either the number or topography of Hoxd loci induced regulatory reallocations affecting both the number and morphology of digits. These results demonstrate why genes located at the extremity of the cluster are expressed at the distal end of the limbs, following a gradual reduction in transcriptional efficiency, and thus highlight the mechanistic nature of collinearity in limbs.

Animals↗
PubMed2002

The orphan nuclear receptor REV-ERBalpha controls circadian transcription within the positive limb of the mammalian circadian oscillator.

Mammalian circadian rhythms are generated by a feedback loop in which BMAL1 and CLOCK, players of the positive limb, activate transcription of the cryptochrome and period genes, components of the negative limb. Bmal1 and Per transcription cycles display nearly opposite phases and are thus governed by different mechanisms. Here, we identify the orphan nuclear receptor REV-ERBalpha as the major regulator of cyclic Bmal1 transcription. Circadian Rev-erbalpha expression is controlled by components of the general feedback loop. Thus, REV-ERBalpha constitutes a molecular link through which components of the negative limb drive antiphasic expression of components of the positive limb. While REV-ERBalpha influences the period length and affects the phase-shifting properties of the clock, it is not required for circadian rhythm generation.

ARNTL Transcription Factors↗
PubMed2002

A t(2;8) balanced translocation with breakpoints near the human HOXD complex causes mesomelic dysplasia and vertebral defects.

Mesomelic dysplasia is a severe shortening of forearms and forelegs, and is found in several distinct human syndromes. Here, we report the cloning of the breakpoints of a human t(2;8)(q31;p21) balanced translocation associated with mesomelic dysplasia of the upper limbs, as well as with vertebral defects. We show that this translocation does not disrupt any gene, hence it most likely exerts its deleterious effect by modifying gene regulation. The HOXD complex lies approximately 60 kb from the translocation breakpoint on chromosome 2. This cluster of genes has an important role in the development of both the vertebral column and the limbs. Only a few cases of mutations of these homeotic genes have been described so far in humans. However, gain- and loss-of-function of Hoxd genes in mice can induce mesomelic dysplasia-like phenotypes, suggesting that misexpression of HOXD genes may indeed be at the origin of this hereditary phenotype.

Arm↗
PubMed2002

Evolutionary conserved sequences are required for the insulation of the vertebrate Hoxd complex in neural cells.

Transcriptional regulation of vertebrate Hox genes involves enhancer sequences located either inside or outside the gene clusters. In the mouse Hoxd complex, for example, series of contiguous genes are coordinately controlled by regulatory sequences located at remote distances. However, in different cellular contexts, Hox genes may have to be insulated from undesirable external regulatory influences to prevent ectopic gene activation, a situation that would likely be detrimental to the developing embryo. We show the presence of an insulator activity, at one extremity of the Hoxd complex, that is composed of at least two distinct DNA elements, one of which is conserved throughout vertebrate species. However, deletion of this element on its own did not detectably affect Hoxd gene expression, unless another DNA fragment located nearby was removed in cis. These results suggest that insulation of this important gene cluster relies, at least in part, upon a sequence-specific mechanism that displays some redundancy.

Animals↗
PubMed2002

A nested deletion approach to generate Cre deleter mice with progressive Hox profiles.

In mice, the loxP/Cre recombinase-dependent system of recombination offers powerful possibilities for engineering genetic configurations of interest. This system can also be advantageously used for conditional mutagenesis in vivo, whenever such an approach is required due to deleterious effects of either one mutation, or a combination thereof. Here, we report on the production of an allelic series of insertions of a Hoxd11/Cre fusion transgene at different positions within the HoxD complex, in order to produce the CRE recombinase with a 'Hox profile' progressively more extended. We used the R26R (R26R) reporter mouse line to functionally assess the distribution and efficiency of the CRE enzyme and discuss the usefulness of these various lines as deleter strains.

Alleles↗
PubMed2002

Developmental biology in Geneva: a three century-long tradition.

It was in the first half of the 18th century when life sciences started to flourish in the independent republic of Geneva. However, it is difficult to identify a genuine school of developmental biologists during that era. Nevertheless, several prominent scientists over the past two and a half centuries have established and maintained a strong tradition of studies in embryological development and reproduction. In this short historical account, we briefly pay tribute to these famous forerunners, by emphasizing both the originality and quality of their work, as well as the many accompanying conceptual and methodological advances. We start with Abraham Trembley (1710-1784) and the discovery of Hydra and of regeneration, and with Charles Bonnet (1720-1793) who, amongst other contributions, first observed parthenogenetic development. In the 19th century, Carl Vogt (1817-1895) and Edouard Claparède (1832-1871) were well-known scientists in this field of research, whereas Hermann Fol (1845-1892) can be considered as one of the pioneers, if not the founder, of causal embryology, through his experiments on lateral asymmetry in manipulated chicken. More recently, Emile Guyénot (1885-1963) and Kitty Ponse (1897-1982) perpetuated this tradition, which is well alive nowadays in the city of Calvin.

Developmental Biology↗