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D Duboule

Publications and source records attributed to D Duboule.

At least 55 records · Page 3Linked to original sources
PubMed1996

Synpolydactyly in mice with a targeted deficiency in the HoxD complex.

The morphogenesis of mammalian digits requires the function of several genes of the HoxD complex during development of limb buds. Using embryonic stem (ES) cells and a site-specific recombination system (loxP/Cre), we have induced a deficiency that eliminates the products of the Hoxd-13, Hoxd-12 and Hoxd-11 genes simultaneously. A Hoxd-11/lacz reporter gene replaced the deleted region in order to monitor the effect of this triple inactivation at the cellular level. Mice homozygous for this deficiency showed small digit primordia, a disorganized cartilage pattern and impaired skeletal mass. These alterations are similar to the defects seen in a human synpolydactyly, suggesting that this syndrome, which is associated with a subtle mutation in HOXD13 (ref. 8), may involve the loss of function of several Hoxd genes. These results indicate the existence of a functional hierarchy among these genes and provide us with an animal model to study human digit malformations.

Animals↗
PubMed1996

In vivo targeted mutagenesis of a regulatory element required for positioning the Hoxd-11 and Hoxd-10 expression boundaries.

Vertebrate Hox genes are required for the proper organization of structures along the rostrocaudal axis. Hoxd-11 is expressed in the posterior part of the embryo, up to the level of prevertebra 27, and its expression boundary is reproduced by a Hoxd-11/lacZ transgene. Expression of this transgene anterior to prevertebra 27 is prevented by the silencing activity of a cis-acting element, region IX. Using transgenic mice, we show that Hoxd-11 repression by region IX is necessary to position the sacrum properly. This silencing activity depends on phylogenetically conserved sequences able to bind in vitro retinoic acid receptors and COUP-TFs. ES cells were used to generate mice carrying a subtle mutation that abolishes binding of nuclear receptors to region IX. Mutant mice display an anterior shift of their lumbosacral transition inherited as a codominant trait. In mutant embryos, expression of both Hoxd-11 and Hoxd-10 mRNAs in the prevertebral column is anteriorized. These results illustrate the sharing, in cis, of a single regulatory element in order to establish the expression boundaries of two neighboring Hoxd genes.

Animals↗
PubMed1996

Gene transpositions in the HoxD complex reveal a hierarchy of regulatory controls.

Vertebrate Hox genes are activated following a temporal sequence that reflects their linear order in the clusters. We introduced two Hoxd transcription units, labeled with lacZ, to an ectopic 5' position in the HoxD complex. Early expression of the relocated genes was delayed and resembled that of the neighboring Hoxd-13. At later stages, locus-dependent expression in distal limbs and the genital eminence was observed, indicating that common regulatory mechanisms are used for several genes. These experiments also illustrated that neighboring genes can share the same cis-acting sequence and that moving genes around in the complex induces novel regulatory interferences. These results suggest that high order regulation controls the activation of Hox genes and highlight three important constraints responsible for the conservation of Hox gene clustering.

Animals↗
PubMed1996

Functional equivalence and rescue among group 11 Hox gene products in vertebral patterning.

Hoxa-11 and Hoxd-11 are paralogous genes required for proper development of the vertebral column, the limbs, and the urogenital system. To further explore the functional relationship between these genes, as well as the potential rescue of one function by the other, we have introduced a Hoxd-11-expressing transgene into Hoxa-11/Hoxd-11 mutant genetic backgrounds. A range of phenotypes was observed, with transgenic mice displaying as few as four lumbar vertebrae while double mutant mice had as many as eight. When transgenic, double homozygote mutant animals showed six lumbar vertebrae, instead of the eight usually observed. The phenotypic rescue of these genotypes shows that the Hoxa-11 and Hoxd-11 products are functionally equivalent and that extra doses of Hoxd-11 can rescue Hoxa-11 loss of function.

Animals↗
PubMed1996

Teleost HoxD and HoxA genes: comparison with tetrapods and functional evolution of the HOXD complex.

In tetrapods, Hox genes are essential for the proper organization and development of axial structures. Experiments involving Hox gene inactivations have revealed their particularly important functions in the establishment of morphological transitions within metameric series such as the vertebral column. Teleost fish show a much simpler range of axial (trunk or appendicular) morphologies, which prompted us to investigate the nature of the Hox system in these lower vertebrates. Here, we show that fish have a family of Hox genes, very similar in both number and general organization, to that of tetrapods. Expression studies, carried out with HoxD and HoxA genes, showed that all vertebrates use the same general scheme, involving the colinear activation of gene expression in both space and time. Comparisons between tetrapods and fish allowed us to propose a model which accounts for the primary function of this gene family. In this model, a few ancestral Hox genes were involved in the determination of polarity in the digestive tract and were further recruited in more elaborate axial structures.

Amino Acid Sequence↗
PubMed1996

Zebrafish Hoxa and Evx-2 genes: cloning, developmental expression and implications for the functional evolution of posterior Hox genes.

Vertebrate Hox genes are required for the establishment of regional identities along body axes. This gene family is strongly conserved among vertebrates, even in bony fish which display less complex ranges of axial morphologies. We have analysed the structural organization and expression of Abd-B related zebrafish HoxA cluster genes (Hoxa-9, Hoxa-10, Hoxa-11 and Hoxa-13) as well as of Evx-2, a gene closely linked to the HoxD complex. We show that the genomic organization of Hoxa genes in fish resembles that of tetrapods albeit intergenic distances are shorter. During development of the fish trunk, Hoxa genes are coordinately expressed, whereas in pectoral fins, they display transcript domains similar to those observed in developing tetrapod limbs. Likewise, the Evx-2 gene seems to respond to both Hox- and Evx-types of regulation. During fin development, this latter gene is expressed as the neighbouring Hox genes, in contrast to its expression in the central nervous system which does not comply with colinearity and extends up to anterior parts of the brain. These results are discussed in the context of the functional evolution of Hoxa versus Hoxd genes and their different roles in building up paired appendages.

Amino Acid Sequence↗
PubMed1996

Function of posterior HoxD genes in the morphogenesis of the anal sphincter.

Vertebrate 5'-located HoxD genes are expressed in the most caudal part of the digestive tract and their potential functions during gut development have been assessed by gene disruptions. We have inserted reporter lacZ sequences within the Hoxd-12 gene and analysed the morphology of the gut in these mice as well as in Hoxd-13 mutant animals. When homozygous, both mutations induce an important disorganization of the anorectal region. In particular, severe alterations of the smooth muscle layers of the rectum led to defective morphogenesis of the internal anal sphincter. Similarly, Hoxd-12 and Hoxd-13 functionally overlap during digit development. The function of these genes in the morphogenesis of the digestive system as well as their functional evolution are discussed.

Anal Canal↗
PubMed1996

[Genetic control of limb development].

Vertebrate limbs are an amazing example of successful adaptation to various environmental conditions. In higher vertebrates, forelimbs help to fly, swim, walk, dig, grasp or play the Passacaille, yet their basic structure (the sequence and spatial arrangement of bony elements) is always the same. This implies the existence of a unique developmental strategy for building a limb (a limb plan) that imposes early on a basic scheme, on the top of which subsequent species-specific customizations will occur. The description of such a universal limb plan, hence the idea that the genetic and developmental processes that generate this plan are very ancient, has been controversial for about a century. It is worth asking whether recent discoveries of important genes involved in these processes can bring novel arguments to the debate.

Animals↗
PubMed1995

Hox gene expression in teleost fins and the origin of vertebrate digits.

Hox genes are essential for growth and patterning of the tetrapod limb skeleton. Mice mutant for the Hoxd-13 gene have an important delay in morphogenesis owing to reduced proliferation. Based on the appearance of atavisms in such mice, we suggested that modifications of Hox gene regulation may have been a source of morphological variation during the evolution of tetrapod limbs. Pectoral and pelvic fins are homologous to fore- and hindlimbs, respectively. To compare the relative importance of Hox genes during fin versus limb morphogenesis, we cloned zebrafish (Danio rerio) HoxD and HoxA complex genes and analysed their expression during fin development. The results suggest a scheme for the fin-limb transition in which the distal autopods (digits) are neomorphic structures produced by unequal proliferation of the posterior part of an ancestral appendix.

Animals↗
PubMed1994

Conservation of a functional hierarchy between mammalian and insect Hox/HOM genes.

We have generated several transgenic Drosophila strains containing different mouse Hox genes under heat shock control and studied how their generalized expression affects Drosophila larval patterns. We find that they have spatially restricted effects which correlate with their genetic order and expression pattern in the mouse; as they are expressed more posteriorly in the mouse, they have more extensive effects in Drosophila. The generalized expressions of Hoxd-8 and d-9 modify Drosophila anterior head segment(s), but have no effect in the rest of the body. Hoxd-10 expression affects head and thorax, but not the abdomen. Finally, Hoxd-11 alters head, thorax not the abdomen. Finally, Hoxd-11 alters head, thorax and abdomen. The developmental effect of the Hox genes consists of a homeotic transformation of the affected segment(s), which exhibit a 'ground' pattern similar to that obtained in the absence of homeotic information, suggesting that Hox genes are able to inactivate Drosophila homeotic genes, but do not specify a pattern of their own. A partial exception is Hoxd-11 which, even though it has a general suppressing effect, can also activate the resident Abdominal-B and empty spiracles genes in ectopic positions. Our results strongly suggest a general conservation of the functional hierarchy of homeotic genes that correlates with genetic order and expression patterns.

Abdomen↗
PubMed1994

Colinearity and functional hierarchy among genes of the homeotic complexes.

Homeotic genes identify structures along the anterior to posterior axis during the development of most animals. These genes are clustered into complexes, and their positions within the cluster correlates with their time of expression and the positions of the anterioposterior boundaries of their expression domains. Functional analyses have revealed that this specific genetic order also coincides with a functional hierarchy among members of these complexes, so that the products of more posterior genes in the cluster tend to be prevalent over those of more anterior genes.

Animals↗
PubMed1994

Expression of the zebrafish gene hlx-1 in the prechordal plate and during CNS development.

The zebrafish hlx-1 gene belongs to the H2.0 subfamily of homeobox genes and is closely related to the mouse Dbx gene with respect to both homeodomain homology (96.7%) and neural expression during embryogenesis. Analysis of hlx-1 expression by in situ hybridization reveals several particularly interesting features. In late gastrula embryos, hlx-1 transcripts are detected within a circular area in the region of the presumptive rostral brain. Subsequently, the expression domain becomes restricted to the hypoblast and undergoes dynamic changes involving conversion into a longitudinal stripe which elongates and retracts following a temporal sequence. The site of transient hlx-1 expression along the ventral midline of the rostral neurectoderm, which in part corresponds to the prechordal plate, suggests a role in the determination of head mesoderm as well as in patterning of the rostral brain. As the midline stripe gradually disappears, the hlx-1 gene becomes regionally expressed within the diencephalon and at a specific dorsoventral level along the hindbrain and spinal cord. In the hindbrain, expression is initiated in dorsoventrally restricted transversal stripes which correlate with the segmental pattern of rhombomeres. The stripes fuse into bilateral columns that are later converted to two series of paired transversal stripes at the rhombomere borders. This pattern is consistent with the proposed subdivision of hindbrain segments into rhombomere centers separated by border regions.

Amino Acid Sequence↗
PubMed1994

Temporal colinearity and the phylotypic progression: a basis for the stability of a vertebrate Bauplan and the evolution of morphologies through heterochrony.

Vertebrate Hox genes are essential for the proper organization of the body plan during development. Inactivation of these genes usually leads to important alterations, or transformations, in the identities of the affected developing structures. Hox genes are activated in a progressive temporal sequence which is colinear with the position of these genes on their respective complexes, so that 'anterior' genes are activated earlier than 'posterior' ones (temporal colinearity). Here, an hypothesis is considered in which the correct timing of activation of this gene family is necessary in order to properly establish the various expression domains. Slight modifications in the respective times of gene activation (heterochronies) may shift expression domains along the rostrocaudal axis and thus induce concurrent changes in morphologies. It is further argued that temporal colinearity only occurs in cells with high mitotic rates, which results in a strong linkage between patterning and growth control and makes the patterning process unidirectional, from anterior, proximal and early, to posterior, distal and late, a model referred to as the 'Einbahnstrasse'. While the nature of the mechanism(s) behind temporal and spatial colinearities is unknown, it is proposed that such a mechanism relies on meta-cis interactions, that is it may necessitate gene contiguity. Such a mechanism would be based on DNA-specific, rather than gene-specific, features such as chromatin configurations or DNA replication. The existence of such a meta-cis mechanism would explain the extraoridinary conservation of this genetic system during evolution as its basic properties would be linked to that of the genetic material itself.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed1994

Developmental expression of the mouse Evx-2 gene: relationship with the evolution of the HOM/Hox complex.

The mouse Evx-2 gene is located in the immediate vicinity of the Hoxd-13 gene, the most posteriorly expressed gene of the HOXD complex. While the Evx-1 gene is also physically linked to the HOXA complex, it is more distantly located from the corresponding Hoxa-13 gene. We have analysed the expression of Evx-2 during development and compared it to that of Evx-1 and Hoxd-13. We show that, even though Evx-2 is expressed in the developing CNS in a pattern resembling that of other Evx-related genes, the overall expression profile is similar to that of the neighbouring limbs and genitalia. We propose that the acquisition of expression features typical of Hox genes, together with the disappearance of some expression traits common to Evx genes, is due to the close physical linkage of Evx-2 to the HOXD complex, which results in Evx-2 expression being partly controlled by mechanisms acting in the HOX complex. This transposition of the Evx-2 gene next to the Hoxd-13 gene may have occurred soon after the large scale duplications of the HOX complexes. A scheme is proposed to account for the functional evolution of eve-related genes in the context of their linkage to the HOM/Hox complexes.

Animals↗
PubMed1994

Differential expression of two different homeobox gene families during mouse tegument morphogenesis.

The expression of six genes belonging to two different homeobox gene families was studied during the embryonic and postnatal morphogenesis of head and body regions of the mouse integument. The first family included the Otx1 and Otx2 genes, both related to the orthodenticle Drosophila gene and the second was represented by four members of the Antennapedia class HOX genes: Hoxc8 and three Hoxd genes, d9, d11 and d13. In situ hybridizations with 35S labeled antisense RNA probes were performed on head serial frontonasal sections, as well as entire embryo and postnatal tail longitudinal sections. The expression of these genes shows a differential spatiotemporal pattern along the cephalo-caudal axis. In 12.5-day and 15.5-day embryos, the Otx2 gene expression is restricted to the nasal epithelium and its associated glands, while the Otx1 transcripts are present in both nasal and facial integuments, including nasal glands and hair vibrissa follicles. The Hoxc8 expression first appears in skin at 14.5 days of gestation in the sternal region and is extended at 16.5 days to the thoracic ventral and lumbar dorsal regions. The Hoxd9 and Hoxd11 genes are only expressed in the caudal skin from 14.5 days of gestation. The Hoxd13 transcripts are the last to appear, 2 days after birth, and are limited to the last epidermal cells to differentiate, i.e. those of the hair matrix of the caudal pelage hair follicles. Taken together, these observations strengthen the hypothesis that different homeobox gene families specify the regional identity of the skin in the cephalic and body regions.

Animals↗
PubMed1993

Disruption of the Hoxd-13 gene induces localized heterochrony leading to mice with neotenic limbs.

Vertebrate Hoxd genes are sequentially activated during the morphogenesis and pattern formation of the limb. Using the approach of gene disruption via homologous recombination in embryonic stem cells, we have assessed the function of the last gene of the complex, Hoxd-13. Mutant mice displayed skeletal alterations along all body axes suggesting the existence of a general multiaxial patterning system. In limbs, abnormalities such as a reduction in the length of some bony elements, loss of phalanges, bone fusions, and the presence of an extra element were observed. We propose that the mutation induces local heterochrony, as illustrated by an important retardation in limb morphogenesis. The relevance of these observations to our understanding of the development and evolution of the tetrapod limb is discussed.

Animals↗