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Biomedical subjects

D Duboule

Publications and source records attributed to D Duboule.

At least 73 records · Page 4Linked to original sources
PubMed1993

Local alterations of Krox-20 and Hox gene expression in the hindbrain suggest lack of rhombomeres 4 and 5 in homozygote null Hoxa-1 (Hox-1.6) mutant embryos.

It is unknown whether cross-regulatory interactions between homeotic genes, which have been shown to play an important role in the maintenance of their expression domains during Drosophila development, are also important during mammalian development. We have analyzed here the expression of Hox genes in Hoxa-1 (Hox-1.6) null mutant embryos to investigate the possible existence of regulatory interactions between Hoxa-1 and other Hox genes. We show that the absence of a functional Hoxa-1 gene product does not globally interfere with the expression of other Hox genes in terms of both spatial boundaries and transcript abundance. However, a limited area of the hindbrain shows a strong reduction in Hoxb-1 (Hox-2.9) and Krox-20 transcripts, which most likely reflects a marked reduction in size of the former fourth and fifth rhombomeres. These alterations coincide with the region that is subsequently affected in Hoxa-1 null mutant mice and suggest that the primary defects in this mutation are spatially restricted deletions of some rhombomeric structures.

Animals↗
PubMed1993

Correlation of expression of Wnt-1 in developing limbs with abnormalities in growth and skeletal patterning.

The Wnt genes are members of a family of vertebrate genes related to the Drosophila gene wingless (wg). They encode secreted molecules that are thought to be important in patterning and growth control during ontogenesis. Several such genes are transcribed in localized domains during limb budding and morphogenesis. We report here a congenital limb malformation in a mouse transgenic line that ectopically expresses Wnt-1 in the developing limbs. The hemizygote phenotype, which is inherited as an autosomal dominant trait, presents extensive distal truncations of skeletal elements, skeletal fusions and interdigital webbing. The data shown here demonstrate that abnormal Wnt-1 expression is correlated with retarded mesenchymal condensations replaced by highly proliferative cells in the limb bud. This seems to lead to an inability of the affected cells to participate in normal skeletal development leading to the adult defects.

Animals↗
PubMed1993

Structure and activity of regulatory elements involved in the activation of the Hoxd-11 gene during late gastrulation.

We have used reporter gene constructs to study the cis regulation of the Hoxd-11 gene (previously Hox-4.6) in transgenic mice. We identified a 5 kb regulatory unit, which was able to reproduce important aspects of the initial activation of the gene along the major body axis. The comparison of the nucleotide sequence of this DNA fragment with the corresponding avian genomic region revealed the presence of seven highly homologous stretches of DNA outside the protein coding regions. In particular, the 3' flanking region contained two such domains that are required to mediate the embryonic activation. A chimeric construct containing the two short homologous regions from the chicken gene could replace the complete murine fragment thus demonstrating that the conserved domains carry the main regulatory elements involved in this activation. The first half of this bipartite regulatory region has enhancer activity when tested with a heterologous promoter, while the second half is required to restrict the enhancer activity to the proper expression domain. These results suggest that stage- and tissue-specific cooperation between regulatory elements is required to control properly the activity of the Hoxd-11 promoter.

Animals↗
PubMed1993

Cooperation of regulatory elements involved in the activation of the Hoxd-11 gene.

We have used lacZ reporter gene constructs to study the cis regulation of the murine Hoxd-11 gene (previously Hox-4.6) in transgenic mice. We identified a genomic region, which was able to simulate important aspects of the developmental regulation of the gene. A short regulatory region, located 3' to the Hoxd-11 transcription unit, was required to mimic initial activation. This regulatory region contains two stretches of DNA, that are highly conserved in the chicken Hoxd-11 3' flanking region. A chimeric construct containing these short homologous regions from the chicken gene could replace the complete murine fragment thus demonstrating that the conserved domains carry the main regulatory elements involved in this activation. The first half of this bipartite regulatory region has positive regulatory activity, while the second half is required to restrict gene expression to the proper posterior domain in the somitic mesoderm. Our results suggest that the control of the Hoxd-11 promoter involves tissue-specific cooperations between regulatory elements.

Animals↗
PubMed1993

The function of Hox genes in the morphogenesis of the vertebrate limb.

The potential of the vertebrate limb as a model system to study developmental mechanisms is particularly well illustrated by the analysis of the Hox gene network. These genes are involved in the establishment of patterns and encode positional information. Their functional organisation during both limb and trunk development are very similar and seem to involve the progressive activation in time, along the chromosome, of a battery of genes whose products could differentially instruct those cells where they are expressed. Thus, cells expressing different Hox genes may behave differently and therefore give rise to various related, but different, structures. The asymmetric distribution of the Hox transcript during limb development likely reflects the final limb asymmetry.

Animals↗
PubMed1992

Targeted misexpression of Hox-4.6 in the avian limb bud causes apparent homeotic transformations.

In the limb bud the 5' members of the Hox-4 gene cluster are expressed in a nested set of overlapping domains which are progressively restricted in the posterior and distal directions. These domains arise early in limb bud development and come to approximate the primordia of the major structural elements of the limb along the anterior/posterior axis (Fig. 1). This pattern, and the fact that surgical manipulations which lead to mirror image duplications along the anterior/posterior axis give rise to mirror image duplications of the domains of expression of these genes, have led to the proposal that these transcription factors specify positional identity along the anterior/posterior axis. Here we test this hypothesis directly using replication-competent retroviral vectors to expand the domain of expression of the Hox-4.6 gene anteriorly during limb development in vivo. We report that alteration of the domain of expression of the Hox-4.6 gene in the developing limb leads to reproducible pattern alterations consistent with a posterior homeotic transformation.

Animals↗
PubMed1992

The vertebrate limb: a model system to study the Hox/HOM gene network during development and evolution.

The potential of the vertebrate limb as a model system to study developmental mechanisms is particularly well illustrated by the analysis of the Hox gene network. These genes are probably involved in the establishment of patterns encoding positional information. Their functional organisation during both limb and trunk development are very similar and seem to involve the progressive activation in time, along the chromosome, of a battery of genes whose products could differentially instruct those cells where they are expressed. This process may be common to all organisms that develop according to an anterior-posterior morphogenetic progression. The possible linkage of this system to a particular mechanism of segmentation as well as its phylogenetic implications are discussed.

Animals↗
PubMed1992

Expression of Hox-4 genes in the chick wing links pattern formation to the epithelial-mesenchymal interactions that mediate growth.

The relationship between the expression of Hox-4 genes in the mesenchyme and the apical ectodermal ridge was investigated in both normal chick wing buds and wing buds treated with retinoic acid. Two conclusions emerge. One is that the activation of Hox-4 domains and the elaboration of Hox-4 gene expression patterns involve cooperation with a signal from the apical ridge. The second is that the domains of expression of 5'-located members of the complex correlate with the maintenance of the thickened ridge which is required for subsequent bud outgrowth.

Animals↗
PubMed1992

Comparison of mouse and human HOX-4 complexes defines conserved sequences involved in the regulation of Hox-4.4.

We have cloned and sequenced, in both mouse and human, regions of the HOX-4 complex which contain two Abd-B like genes, Hox-4.4 and Hox-4.5 (HOX4C and HOX4D in human, respectively). The high degree of conservation between the homeoprotein sequences extends to non-coding areas, which suggests that the mechanisms of regulation have been conserved. We show that the Hox-4.5/Hox-4.4 intergenic region can be broadly subdivided into three domains based on DNA conservation between rodents and primates. The presence of all these domains in association with sequences located 3' to the transcription termination site are required to mimick the spatial regulation of Hox-4.4 in transgenic mouse embryos. Several highly conserved short sequences located in this region were studied in gel retardation assays for their binding to potential regulatory factors. One such factor is detected in embryonal carcinoma cells but absent from other differentiated cell lines. This specific binding activity is down regulated upon retinoic acid treatment.

Amino Acid Sequence↗
PubMed1992

Homeobox genes and pattern formation in the vertebrate limb.

The developing vertebrate limb is a powerful system to study genes potentially involved in pattern formation. Many such candidate genes encode transcription factors belonging to the class of the "homeodomain" proteins. In this short review, we discuss the possible functions of different subfamilies of homeobox genes. Genes belonging to the Hox family (related to the Drosophila homoeotic genes), such as the HOX-1, HOX-3, and HOX-4, complexes are probably among those encoding the patterning information. Their differential expression in the mesenchymal compartment is proposed to be responsible for the determination of the various axial elements. Other homeobox-containing genes are expressed in both the mesenchyme of the progress zone and the ectodermal ridge. These genes, Hox-7.1 and Hox-8.1, are related to the Drosophila msh gene and could be involved in epithelial-mesenchymal interactions linking the growth of the system to its patterning.

Animals↗
PubMed1992

Regional expression of the homeobox gene Nkx-2.2 in the developing mammalian forebrain.

A novel mouse homeobox-containing gene, Nkx-2.2, has been isolated. Nkx-2.2 is a member of a family of genes whose homeodomains are homologous to that of the Drosophila NK-2 gene. Nkx-2.2 transcripts are found in localized domains of the brain during mouse embryogenesis. Nkx-2.2 expression in the brain abuts and partially overlaps with the expression domains of two other related homeobox-containing genes, TTF-1 and Dlx. The expression domains of the three genes in the developing prosencephalon coincide with anatomical boundaries, particularly apparent in the diencephalon. This result raises the possibility that these genes may specify regional differentiation of the developing diencephalon into its anatomically and functionally defined subregions. Nkx-2.2 may be involved in specifying diencephalic neuromeric boundaries.

Animals↗
PubMed1992

Expression of the murine Dlx-1 homeobox gene during facial, ocular and limb development.

We have analysed the expression pattern of the mouse homeobox containing gene Dlx-1. This gene harbors a homeodomain related to that found in the Drosophila distal-less (dll) gene. In addition to its expression in the developing forebrain, Dlx-1 is transcribed in several structures containing cells of neural crest origin such as the facial mesenchyme and various elements of the peripheral nervous system. Dlx-1 transcripts are also detected in the differentiating retina and during limb morphogenesis, in the apical ectodermal ridge. The possible involvement of Dlx-1 during facial, ocular and limb development is discussed.

Animals↗
PubMed1992

The mis-expression of posterior Hox-4 genes in talpid (ta3) mutant wings correlates with the absence of anteroposterior polarity.

Developing chicken wings homozygous for the talpid (ta3/ta3) mutation are polydactylous and have defects in the establishment of their anteroposterior polarity. We analysed the expression domains of the posteriorly restricted homeobox Hox-4 genes in such mutant wings. The Hox-4 genes are now expressed right across the anteroposterior axis instead of being expressed just posteriorly. This correlates well with the absence of clear morphological differences between the talpid3 digits and reinforces the idea that vertebrate Hox-4 genes are involved in setting up the limb anteroposterior asymmetry.

Animals↗
PubMed1992

Hox-4 gene expression in mouse/chicken heterospecific grafts of signalling regions to limb buds reveals similarities in patterning mechanisms.

The products of Hox-4 genes appear to encode position in developing vertebrate limbs. In chick embryos, a number of different signalling regions when grafted to wing buds lead to duplicated digit patterns. We grafted tissue from the equivalent regions in mouse embryos to chick wing buds and assayed expression of Hox-4 genes in both the mouse cells in the grafts and in the chick cells in the responding limb bud using species specific probes. Tissue from the mouse limb polarizing region and anterior primitive streak respecify anterior chick limb bud cells to give posterior structures and lead to activation of all the genes in the complex. Mouse neural tube and genital tubercle grafts, which give much less extensive changes in pattern, do not activate 5'-located Hox-4 genes. Analysis of expression of Hox-4 genes in mouse cells in the grafted signalling regions reveals no relationship between expression of these genes and strength of their signalling activity. Endogenous signals in the chick limb bud activate Hox-4 genes in grafts of mouse anterior limb cells when placed posteriorly and in grafts of mouse anterior primitive streak tissue. The activation of the same gene network by different signalling regions points to a similarity in patterning mechanisms along the axes of the vertebrate body.

Animals↗
PubMed1991

A mouse gene related to Distal-less shows a restricted expression in the developing forebrain.

Many genes known to be involved in embryogenesis and morphogenesis of the fruitfly Drosophila melanogaster encode proteins with a highly conserved region of 60 amino acids called the homeodomain. Mammalian counterparts for most of these genes have been identified, including those homologous to the Drosophila homeotic genes or to genes such as evenskipped, engrailed or caudal. We have isolated a murine homeobox gene that encodes a homeodomain similar to that encoded by the Drosophila Distalless (Dll) gene. Dll has a crucial role in Drosophila limb morphogenesis, partially specifying pattern along the proximo-distal axis of the limb. The murine counterpart is expressed in a restricted region of the developing brain, within the diencephalon and the adjacent telencephalic regions.

Amino Acid Sequence↗
PubMed1991

Expression of the homeobox Hox-4 genes and the specification of position in chick wing development.

The chicken Hox-4 homeogenes, like those of the mouse, are coordinately expressed in partially overlapping domains during wing development. Local application of retinoic acid, a putative endogenous morphogen, induces de novo transcription of Hox-4 genes. The mirror-image patterns of Hox-4 gene expression, which are obtained in this way, correlate with the subsequent development of mirror-image patterns of digits. Hox-4 genes probably encode positional information.

Amino Acid Sequence↗