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Biomedical subjects

D Duboule

Publications and source records attributed to D Duboule.

At least 91 records · Page 5Linked to original sources
PubMed1991

HOX4 genes encode transcription factors with potential auto- and cross-regulatory capacities.

We have looked for the binding of several HOX4 complex homeoproteins in the genomic region containing the HOX4C promoter, between the human HOX4C and HOX4D genes. The HOX4C, HOX4D and Hox-4.3 homeoproteins bind to a phylogenetically highly conserved DNA fragment, which is located in the proximal part of this intergenic region and contains multiple binding sites for these HOX4 proteins. Using cotransfection experiments, we show that this endogenous DNA sequence can mediate transactivation by the HOX4D and HOX4C proteins and that this effect requires the presence of TAAT-related binding sites. The Hox-4.3 protein, in contrast, is unable to activate and can repress the activation observed with the two other proteins. These results show that the HOX4D and HOX4C genes are genuine sequence-specific transcription factors and suggest that, as in Drosophila, cross-regulatory interactions between these genes might be essential for their proper expression.

3T3 Cells↗
PubMed1991

Murine genes related to the Drosophila AbdB homeotic genes are sequentially expressed during development of the posterior part of the body.

The cloning, characterization and developmental expression patterns of two novel murine Hox genes, Hox-4.6 and Hox-4.7, are reported. Structural data allow us to classify the four Hox-4 genes located in the most upstream (5') position in the HOX-4 complex as members of a large family of homeogenes related to the Drosophila homeotic gene Abdominal B (AbdB). It therefore appears that these vertebrate genes are derived from a selective amplification of an ancestral gene which gave rise, during evolution, to the most posterior of the insect homeotic genes so far described. In agreement with the structural colinearity, these genes have very posteriorly restricted expression profiles. In addition, their developmental expression is temporally regulated according to a cranio-caudal sequence which parallels the physical ordering of these genes along the chromosome. We discuss the phylogenetic alternative in the evolution of genetic complexity by amplifying either genes or regulatory sequences, as exemplified by this system in the mouse and Drosophila. Furthermore, the possible role of 'temporal colinearity' in the ontogeny of all coelomic (metamerized) metazoans showing a temporal anteroposterior morphogenetic progression is addressed.

Amino Acid Sequence↗
PubMed1991

The Hox-4.8 gene is localized at the 5' extremity of the Hox-4 complex and is expressed in the most posterior parts of the body during development.

We report the isolation and expression pattern of a novel mouse homeobox gene, Hox-4.8. Hox-4.8 is the most 5'-located homeobox gene in the HOX-4 complex. Sequence analysis confirmed that Hox-4.8 is a member of the subfamily of AbdominalB-related Hox-4 genes and revealed strong interspecies conservation. As for the human locus, Hox-4.8 is probably the last Hox gene in this part of the HOX-4 complex. During development, Hox-4.8 transcripts are restricted to the extremities of the embryonic anteroposterior axis and limbs as well as in the developing tail bud and to the most posterior segment of the gut (the rectum). Within the limb mesenchyme, Hox-4.8 is expressed in more posterodistal regions than those of its neighbour Hox-4.7. Hence, Hox-4.8 expression appears to be related to the last significant phenotypic changes towards the extremities of the embryonic body and limb axes.

Amino Acid Sequence↗
PubMed1991

Patterning in the vertebrate limb.

The past few years have seen the isolation and characterization of some of the genes involved in the control of limb pattern formation. Their possible role in this fundamental process is discussed in the light of recent data, and an attempt is made to superimpose this molecular approach to patterning on pre-existing conceptual views.

Animals↗
PubMed1991

HOX-4 genes and the morphogenesis of mammalian genitalia.

We examined the temporal and spatial expression patterns of the homeo box HOX-4 complex genes during the morphogenesis of the genitalia of mice. The results show that only those Hox-4 genes that are expressed very posteriorly in the trunk, or very distally in the limbs, seem to be involved in the patterning of the genital tubercle. This is consistent with the idea of "temporal colinearity", which suggests that the very last structure to require patterning during vertebrate development will express Hox genes located at the 5' extremity of the HOX complexes. We also show that genital tubercle mesenchyme can respecify pattern in the chicken wing bud. This finding reinforces the concept of the uniformity in the patterning mechanisms along the various axes of the body.

Animals↗
PubMed1990

The segment-specific gene Krox-20 encodes a transcription factor with binding sites in the promoter region of the Hox-1.4 gene.

Krox-20 is a mouse zinc finger gene expressed in a segment-specific manner in the early central nervous system, which makes it a potential developmental control gene. In this report, we show that the Krox-20 protein binds in vitro to two specific DNA sites located upstream from the homeobox containing gene Hox-1.4. The nucleotide sequence recognized by Krox-20 is closely related to the Sp1 target sequence, which is consistent with the similarity existing between the zinc fingers of the two proteins. In co-transfection experiments in cultured cells, Krox-20 dramatically activates transcription from the herpes simplex virus thymidine kinase promoter when an oligomer of its binding site is present in cis close to the promoter. Analysis of mutated binding sites demonstrates that the level of activation by Krox-20 correlates with the affinity of the protein for the mutant sequence. These data indicate that Krox-20 constitutes a sequence-specific DNA-binding transcription factor. Parallel analysis of the expression of Krox-20 and Hox-1.4 in the neural tube by in situ hybridization revealed no overlap, arguing against direct interactions between these two genes. The possible involvement of Krox-20 in the regulation of the transcription of other homeobox genes is discussed in view of their respective patterns of expression.

Animals↗
PubMed1990

The murine genes Hox-5.1 and Hox-4.1 belong to the same HOX complex on chromosome 2.

Two different loci of Antennapedia-related homeobox-containing genes have been shown to map to mouse chromosome 2: the HOX-5 complex and the Hox-4.1 gene. These independently derived loci are likely to be parts of a single gene complex, although their close linkage has not yet been demonstrated. Since cosmid walks to extend the HOX-5 cluster and to potentially link the two loci were unsuccessful, we have used large restriction fragments separated by pulsed-field gel electrophoresis to demonstrate the linkage between probes from the HOX-5 region and sequences near Hox-4.1. To further define the distance between the two linked loci, we screened a NotI jumping library with sequences near the Hox-5.1 gene to obtain a marker within the region predicted to contain Hox-4.1. The jumping endpoint lies within genomic clones from a lambda phage walk extending from the 5' end of Hox-4.1, and thus provides clear evidence of linkage between the two Hox loci. Our results demonstrate that Hox-4.1 lies approximately 35 kb downstream of the Hox-5.1 gene and that the two loci do indeed thus constitute parts of the same HOX complex.

Animals↗
PubMed1990

A molecular genetic linkage map of mouse chromosome 2.

Interspecific backcross mice were used to create a molecular genetic linkage map of chromosome 2. Genomic DNAs from N2 progeny were subjected to Southern blot analysis using molecular probes that identified the Abl, Acra, Ass, C5, Cas-1, Fshb, Gcg, Hox-5.1, Jgf-1, Kras-3, Ltk, Pax-1, Prn-p, and Spna-2 loci; these loci were added to the 11 loci previously mapped to the distal region of chromosome 2 in the same interspecific backcross to generate a composite multilocus linkage map. Several loci mapped near, and may be the same as, known mutations. Comparisons between the mouse and the human genomes indicate that mouse chromosome 2 contains regions homologous to at least six human chromosomes. Mouse models for human diseases are discussed.

Animals↗
PubMed1990

The HOX-5 and surfeit gene clusters are linked in the proximal portion of mouse chromosome 2.

Using an interspecies backcross, we have mapped the HOX-5 and surfeit (surf) gene clusters within the proximal portion of mouse chromosome 2. While the HOX-5 cluster of homeobox-containing genes has been localized to chromosome 2, bands C3-E1, by in situ hybridization, its more precise position relative to the genes and cloned markers of chromosome 2 was not known. Surfeit, a tight cluster of at least six highly conserved "housekeeping" genes, has not been previously mapped in mouse, but has been localized to human chromosome 9q, a region of the human genome with strong homology to proximal mouse chromosome 2. The data presented here place HOX-5 in the vicinity of the closely linked set of developmental mutations rachiterata, lethargic, and fidget and place surf close to the proto-oncogene Abl, near the centromere of chromosome 2.

Animals↗
PubMed1990

Primary structure and embryonic expression pattern of the mouse Hox-4.3 homeobox gene.

We report the cloning, genomic localization, primary structure and developmental expression pattern of the novel mouse Hox-4.3 gene. This gene is located within the HOX-4(5) complex, at a position which classifies it as a member of the Hox-3.1 and -2.4 subfamily, the DNA and predicted protein sequences further confirmed this classification. Hox-4.3 has a primary structure characteristic of a Hox gene but, in addition, contains several monotonic stretches of amino acids, one of the 'paired'-like type. As expected from its presence and position within the complex. Hox-4.3 is developmentally expressed in structures of either mesodermal or neurectodermal origin located or derived from below a precise craniocaudal level. However, a very important offset between anteroposterior boundaries within neuroectoderm versus mesoderm derivatives is observed. Like other genes of the HOX-4(5) complex, Hox-4.3 is expressed in developing limbs and gonads, suggesting that 'cluster specificity' could be a feature of the HOX network.

Amino Acid Sequence↗
PubMed1989

Coordinate expression of the murine Hox-5 complex homoeobox-containing genes during limb pattern formation.

The homoebox-containing genes of the Hox-5 complex are expressed in different but overlapping domains in limbs during murine development. The more 5' the position of these genes in the complex, the later and more distal is their expression. Antero-posterior differences are also observed. A model is proposed that accounts for the establishment of these expression domains in relation to the existence of a morphogen released by the zone of polarizing activity. Comparison of these observations with the expression patterns of the genes of Hox complexes in the early embryo suggests that similar molecular mechanisms are involved in the positional signalling along the axes of both the embryonic trunk and the fetal limbs.

Animals↗
PubMed1989

The structural and functional organization of the murine HOX gene family resembles that of Drosophila homeotic genes.

This paper reports the cloning of the fourth major murine homeogene complex, HOX-5. The partial characterization of this gene cluster revealed the presence of two novel genes (Hox-5.2, Hox-5.3) located at the 5' extremity of this complex. In situ hybridization experiments showed that these two genes are transcribed in very posterior domains during embryonic and foetal development. We also show that Hox-1.6, the gene located at the 3' most position in the HOX-1 complex, has a very anterior expression boundary during early development. These results clearly support the recently proposed hypothesis that the expression of murine Antp-like homeobox-containing genes along the antero-posterior developing body axis follows a positional hierarchy which reflects their respective physical positions within the HOX clusters, similar to that which is found for the Drosophila homeotic genes. Such a structural and functional organization is likely conserved in most vertebrates. Moreover, on the basis of sequence comparisons, we propose that the ordering of homeobox-containing genes within clusters has been conserved between Drosophila and the house mouse. Thus, very different body plans might be achieved, both in insects and vertebrates, by evolutionarily conserved gene networks possibly displaying similar regulatory interactions.

Amino Acid Sequence↗
PubMed1989

Two gene members of the murine HOX-5 complex show regional and cell-type specific expression in developing limbs and gonads.

This study reports the expression domains of two murine HOX gene members of the HOX-5 complex (Hox-5.2, Hox-5.3). These two genes have very similar homeodomain sequences, as well as temporal and spatial specificities of expression. They are both expressed at very posterior levels in the central nervous system, in sclerotome derivatives and in a few internal organs. In addition to these expression domains which are shared with other HOX genes, transcripts from both Hox-5.2 and Hox-5.3 are present at high levels in developing limbs. After an early homogeneous expression in mesodermal limb bud cells, transcription becomes restricted to cartilage-differentiating cells. In addition, Hox-5.2 is a marker for gonadal development. The possible involvement of such genes during inductive processes or organogenesis is discussed.

Amino Acid Sequence↗
PubMed1989

Mouse homeo-genes within a subfamily, Hox-1.4, -2.6 and -5.1, display similar anteroposterior domains of expression in the embryo, but show stage- and tissue-dependent differences in their regulation.

By use of in situ hybridization experiments on mouse embryo sections, we compare the transcript patterns of three homeo-genes from the Hox-1.4 subfamily (Hox-1.4, -2.6 and -5.1). Genes within a subfamily are true homologues, present in the genome as a result of duplication of an ancestral homeo-gene cluster. We show that Hox-1.4, -2.6 and -5.1 are similar, although apparently not identical, in the limits of their transcript domains along the anteroposterior axis. Within the prevertebral column of the 12 1/2 day embryo, for example, the anterior boundary of transcripts for each of the three genes was most obvious at the junction of the first and second prevertebrae. Similarly, all three genes showed an anterior boundary of transcripts within the central nervous system that was located in the mid-myelencephalon of the hindbrain. Both in the prevertebral column and hindbrain, however, Hox-2.6 and Hox-5.1 transcripts extended slightly anterior to the anteriormost limits detected for Hox-1.4. In spite of close similarities in the positions of their transcript domains, Hox-1.4, -2.6 and -5.1 displayed striking stage- and tissue-dependent differences in the relative abundance of their transcripts. For example, Hox-5.1 transcripts were abundant within mesoderm and ectoderm of early stages (8 1/2 and 9 1/2 days), yet were detected only weakly in mesodermal components of the lung and stomach at 10 1/2 days, and were apparently absent from these tissues at 12 1/2 days. In contrast, Hox-1.4 and Hox-2.6 transcripts were relatively weakly detected at 8 1/2 and 9 1/2 days, but were abundant within the lung and stomach at 12 1/2 days. Our findings suggest, but do not prove, that genes within the Hox-1.4 subfamily might be coordinately regulated in their expression. We discuss the patterns of mouse homeo-gene expression now observed in terms of models originally devised for Drosophila. We also propose how our new findings may help to explain any selective advantage to the vertebrates of homeo-gene duplication to form subfamilies.

Animals↗
PubMed1989

The mouse Hox-1.4 gene: primary structure, evidence for promoter activity and expression during development.

This study reports the structure of the mouse homeobox-containing gene Hox-1.4 of the HOX-1 cluster, as well as its expression pattern during embryonic and fetal development. The overall structure of this gene includes two major exons, the second of which encodes the homeo-domain. The putative Hox-1.4 protein displays similarities with products of homologous genes located at the same relative positions in other HOX clusters. A fragment extending 360 base pairs (bp) upstream of a transcriptional start site was shown to be able to promote transcription in transfected cells. This fragment is GC-rich and contains binding sites for the Sp1 transcription factor. In situ hybridization studies revealed the Hox-1.4 expression pattern during development. As already reported for several other murine Hox genes, Hox-1.4 is expressed in the fetal central nervous system (CNS), in structures derived from somitic mesodermal condensations (sclerotomes, prevertebrae) as well as in several mesodermal components of various organs and structures such as lungs, gut, stomach, intestine and meso- and metanephros. This expression pattern is in good agreement with recent proposals concerning the involvement of such genes in the establishment of the vertebrate body plan as well as the relationship between the positions of these genes within their clusters and the anteroposterior restriction of their expression domains.

Amino Acid Sequence↗
PubMed1988

Hox-5.1 defines a homeobox-containing gene locus on mouse chromosome 2.

We have isolated a murine homeobox-containing gene, Hox-5.1, by virtue of its relatedness to the Hox-1.4 gene. In situ hybridization to metaphase spreads mapped Hox-5.1 to band D of mouse chromosome 2. Sequence comparisons indicate that Hox-5.1 is the murine homolog of the human C13 homeobox-containing gene. Hox-5.1 also bears significant similarity to the Xenopus Xhox-1A homeobox-containing gene and the Drosophila deformed homeotic gene at N-terminal and homeobox regions. Hox-5.1 transcripts were detected in mouse embryos, in adult mouse testis, kidney, heart, and intestine, and in mouse embryonal carcinoma cells treated with retinoic acid. In situ hybridization to sections from whole mouse embryos revealed Hox-5.1 expression in spinal cord and prevertebrae.

Amino Acid Sequence↗
PubMed1987

Hox-1.6: a mouse homeo-box-containing gene member of the Hox-1 complex.

Hox-1.6, a mouse homeo-box-containing gene member of the Hox-1 complex, is described. The Hox-1.6 homeo-box shows more divergence than the other members of the complex with the Drosophila Antennapedia-like homeo-box class. This previously undescribed gene was studied with respect to its transcription pattern and was found to be expressed during mouse fetal development in an intestine-specific manner in adults, and in tumours or cell types exhibiting early endodermal-like differentiation. The study of embryonic partial Hox-1.6 cDNA clones revealed structural features common to other Drosophila and vertebrate homeo-box-containing genes, but also indicated that Hox-1.6 transcripts might display splicing patterns more complex than those known for other vertebrate homeo-genes. One of these cDNA clones contains a rather short open reading frame which would encode a protein of approximately 14.5 kd. The use of this clone as a probe for S1 nuclease mapping confirmed that different Hox-1.6 transcripts were present both in embryonic total RNA and in embryonal carcinoma cell cytoplasmic RNA. These various transcripts are probably generated by an alternative splicing mechanism and may thus encode a set of related proteins.

Amino Acid Sequence↗