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Biomedical subjects

E Boncinelli

Publications and source records attributed to E Boncinelli.

At least 109 records · Page 6Linked to original sources
PubMed1992

Two vertebrate homeobox genes related to the Drosophila empty spiracles gene are expressed in the embryonic cerebral cortex.

We cloned two homeobox genes, Emx1 and Emx2, related to empty spiracles, a gene expressed in very anterior body regions during early Drosophila embryogenesis, and studied their expression in mouse embryos. Emx1 expression is detectable from day 9.5 of gestation whereas Emx2 appears to be already expressed in 8.5 day embryos. Both genes are expressed in the presumptive cerebral cortex and olfactory bulbs. Emx1 is expressed exclusively there, whereas Emx2 is also expressed in some neuroectodermal areas in embryonic head including olfactory placodes in earlier stages and olfactory epithelia later in development.

Amino Acid Sequence↗
PubMed1992

Modulation of HOX2 gene expression following differentiation of neuronal cell lines.

The expression of the genes in the human HOX2 locus has been studied during differentiation of two human neuroblastoma (SH-SY5Y and Kelly), a human glioblastoma (251-MG), and the murine F9 embryonal carcinoma cell lines. Cells were differentiated with retinoic acid (RA), or with RA together with dibutyral cyclic AMP (db-cAMP) and nerve growth factor (NGF) in order to assess the changes in the expression patterns of these homeobox genes during neuronal differentiation. We show that the genes of the HOX2 locus are expressed in a complex transcription pattern that varies with cell type. The two uninduced neuroblastoma cell lines show a similar pattern of expression for a number of HOX2 genes although the levels of expression are different for individual cell lines. The embryonal carcinoma cell line F9 expresses low levels of several HOX2 genes which is restricted to the 5' region of the HOX2 cluster. The glioblastoma cell line, 251-MG expresses almost all of the genes of the HOX2 locus. Differentiation of these cells modulates the expression of the HOX2 genes in a manner that is dependent upon the cell type as well as the differentiation factor. Differentiation affects both the level of HOX2 gene expression and the distribution of transcript sizes. In conclusion, our analysis reveals a complex pattern of expression for the genes of the HOX2 locus in neuronal and glial cells and suggests that the cell-specific expression of these genes may be correlated with the phenotypic differences that are observed between different neuronal and glial cell populations within the nervous system.

Animals↗
PubMed1992

Xenopus Hox-2 genes are expressed sequentially after the onset of gastrulation and are differentially inducible by retinoic acid.

In this paper, we review experiments to characterise the developmental expression and the responses to all-trans retinoic acid (RA) of six members of the Hox-2 complex of homeobox-containing genes, during the early development of Xenopus laevis. We showed that the six genes are expressed in a spatial sequence which is colinear with their putative 3' to 5' chromosomal sequence and that five of them are also expressed rapidly after the beginning of gastrulation, in a 3' to 5' colinear temporal sequence. The sixth gene (Xhox2.9) has an exceptional spatial and temporal expression pattern. The six genes all respond to RA by showing altered spatiotemporal expression patterns, and are also RA-inducible, the sequence of the magnitudes of their RA responses being colinear with their 3' to 5' chromosomal sequence, and with their spatial and temporal expression sequences. Our data also reveal that there is a pre-existing anteroposterior polarity in the embryo's competence for a response to RA. These results complement and extend previous findings made using murine and avian embryos and mammalian cell lines. They suggest that an endogenous retinoid could contribute to positional information in the early Xenopus embryo.

Animals↗
PubMed1991

Erythroid-restricted expression of homeobox genes of the human HOX 2 locus.

We have previously reported that certain members of the HOX 1 and HOX 2 clusters of class 1 homeobox-containing genes showed lineage-restricted patterns of expression in a small series of human hematopoietic cell lines. We now report on the expression patterns of the entire HOX 2 cluster, consisting of nine homeobox genes, in a broad survey of leukemic cell lines of different phenotypes. The most striking observation is that all but one of the HOX 2 genes are consistently expressed in cells with erythroid character and/or potential, but, with rare exception, not in cells with myelomonocytic or T- or B-lymphoid phenotype. By contrast, several genes of the HOX 1 and 3 loci are not expressed in erythroid lines. Within erythroid cell lines, many of the HOX 2 genes are expressed as multiple transcripts. Expression of some HOX 2 genes is detectable in normal human marrow. These data show that in human hematopoietic cell lines HOX 2 homeobox gene expression is largely restricted to cells of erythroid phenotype and suggest that these genes play a role in erythropoiesis.

Blotting, Northern↗
PubMed1991

A distinct Hox code for the branchial region of the vertebrate head.

The branchial region of the vertebrate head forms through complex interactions involving rhombomeric segments, neural crest and branchial arches. It is though that aspects of their patterning mechanisms are linked and involve Hox-2 genes, whose overlapping and spatially restricted expression domains represent a combinatorial code for generating regional diversity. Vertebrates possess four Hox clusters of Antennapedia class homeobox genes, related to each other by duplication and divergence from a common ancestral complex. In consequence, at equivalent positions in different clusters there are highly related genes known as subfamilies or paralogous groups. As Hox-2 genes cannot fully account for patterning individual rhombomeres, we investigated whether offsets in expression limits of paralogous genes could account for the generation of regional diversity. We report here that, with the exception of the labial subfamily, paralogues show identical expression limits in rhombomeres, cranial ganglia and branchial arches, providing a combinatorial Hox code for the branchial region that seems to be different in organization to that of the trunk.

Alleles↗
PubMed1991

Coordinate regulation of HOX genes in human hematopoietic cells.

Hematopoiesis is a continuous process in which precursor cells proliferate and differentiate throughout life. However, the molecular mechanisms that govern this process are not clearly defined. Homeobox-containing genes, encoding DNA-binding homeodomains, are a network of genes highly conserved throughout evolution. They are organized in clusters expressed in the developing embryo with a positional hierarchy. We have analyzed expression of the four human HOX loci in erythroleukemic, promyelocytic, and monocytic cell lines to investigate whether the physical organization of human HOX genes reflects a regulatory hierarchy involved in the differentiation process of hematopoietic cells. Our results demonstrate that cells representing various stages of hematopoietic differentiation display differential patterns of HOX gene expression and that HOX genes are coordinately switched on or off in blocks that may include entire loci. The entire HOX4 locus is silent in all lines analyzed and almost all the HOX2 genes are active in erythroleukemic cells and turned off in myeloid-restricted cells. Our observations provide information about the regulation of HOX genes and suggest that the coordinate regulation of these genes may play an important role in lineage determination during early steps of hematopoiesis.

Cell Line↗
PubMed1991

HOX gene activation by retinoic acid.

Vertebrate homeobox genes of the Hox family are, like Drosophila homeotic genes, organized in gene clusters and show a strict correspondence, or collinearity, between the order of the genes (3' to 5') within the chromosomal cluster and that of their expression domains (anterior to posterior) in the embryo. Recent data obtained from embryonal carcinoma cells induced to differentiate by retinoic acid cast some light on the molecular mechanisms underlying the collinear expression of the Hox genes.

Amino Acid Sequence↗
PubMed1991

EVX2, a human homeobox gene homologous to the even-skipped segmentation gene, is localized at the 5' end of HOX4 locus on chromosome 2.

We isolated and mapped three new human homeoboxes located on chromosome 2 upstream from the reported seven HOX4 homeobox sequences. Two of them, HOX41 and HOX4H, clearly belong to the HOX gene family, in particular to homology groups 1 and 2, and possibly represent the most 5' HOX4 homeoboxes. A third homeobox 13 kb upstream from HOX41 was identified. Sequencing data show that this is the human homolog of the murine Evx-2 homeobox. Both homeoboxes are closely related to the murine Evx-1 and to the frog Xhox-3 homeoboxes. The four genes represent vertebrate homologs of Drosophila even-skipped (eve), a segmentation gene of the pair-rule class. Human EVX2 sequences belong to an active gene because they are transcribed and properly processed in cells and tissues. We have identified for the first time a homeogene of a different class at a HOX locus. These findings are relevant to the understanding of the evolution of HOX gene clusters and their regulation.

Amino Acid Sequence↗
PubMed1991

Differential regulation by retinoic acid of the homeobox genes of the four HOX loci in human embryonal carcinoma cells.

We studied the expression of 38 human homeobox genes belonging to the four HOX complex loci in embryonal carcinoma (EC) cells induced to differentiate by culturing them in a medium containing retinoic acid (RA). Genes located at the 3' end of each one of the four HOX loci are activated by RA in a sequential order colinear with their 3' to 5' arrangement in the cluster: 3' HOX genes respond early to the drug while upstream genes respond progressively later. Among the genes located at the 5' end of HOX loci RNase protection analysis reveals that one HOX3 gene and four HOX4 genes are weakly expressed in EC stem cells and downregulated upon treatment with 10(-5) M RA. While activation of early responding genes does not require continuous protein synthesis, the observed timing and polarity of gene activation is disrupted in the absence of protein synthesis.

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

Alteration of homeobox gene expression by N-ras transformation of PA-1 human teratocarcinoma cells.

We used a series of cell clones from a human teratocarcinoma cell line, PA-1, to study the effect of transformation by an activated N-ras oncogene on the expression of genes involved in retinoic acid (RA)-induced differentiation and growth regulation. Recently, it has been shown that expression of human HOX 2 genes is sequentially activated by RA beginning from Hox 2.9 at the 3' end of the HOX 2 cluster (A. Simeone, D. Acampora, L. Arcioni, P. W. Andrews, E. Boncinelli, and F. Mavilio, Nature [London] 346:763-766, 1990). We now report that six different genes of the cluster HOX 1 are sequentially induced by RA in a similar temporal pattern, beginning with genes at the 3' end of the cluster. However, in N-ras-transformed cell clones, RA-induced expression of these homeobox genes is delayed. Hox 1.4 and Hox 1.3, genes abundantly induced in nontransformed clones after 3 days of RA treatment, are expressed in N-ras-transformed cells only after 10 days of RA treatment. At this time, the cells' growth is arrested at very high density, and no differentiated morphologic characteristics are observed. Constitutive expression of a transfected Hox 1.4 gene under the control of a simian virus 40 promotor leads to differentiated cell morphology similar to that of the RA-induced phenotype and restores the growth-inhibitory effects of RA in N-ras-transformed cells. These observations provide evidence that enhanced proliferation in N-ras-transformed cells compromises teratocarcinoma cell differentiation by a mechanism that transiently suppresses homeobox gene induction and implies a central role for homeobox genes in RA-induced cell differentiation. We conclude that stimulation of a putative growth factor signal pathway, associated with ras-induced proliferation, transiently suppresses the induction of transcription factors functionally involved in cell growth and differentiation.

Amino Acid Sequence↗
PubMed1990

Sequential activation of HOX2 homeobox genes by retinoic acid in human embryonal carcinoma cells.

RETINOIC acid had been implicated as a natural morphogen in chicken and frog embryogenesis, and is presumed to act through the gene regulatory activity of a family of nuclear receptors. Homeobox genes, which specify positional information in Drosophila and possibly in vertebrate embryogenesis, are among the candidate responsive genes. We previously reported that retinoic acid specifically induces human homeobox gene (HOX) expression in the embryonal carcinoma cell line NT2/D1. We now show that the nine genes of the HOX2 cluster are differentially activated in NT2/D1 cells exposed to retinoic acid concentrations ranging from 10(-8) to 10(-5) M. Genes located in the 3' half of the cluster are induced at peak levels by 10(-8) M retinoic acid, whereas a concentration of 10(-6) to 10(-5) M is required to fully activate 5' genes. At both high and low retinoic acid concentrations, HOX2 genes are sequentially activated in embryonal carcinoma cells in the 3' to 5' direction.

Antigens, Surface↗
PubMed1990

Molecular mechanisms underlying the expression of the human HOX-5.1 gene.

The complex mechanisms underlying homeobox genes expression involve regulation at transcriptional, post-transcriptional and translational levels. The multiple transcripts of the human HOX-5.1 gene are expressed differentially in tissue- and stage-specific patterns during embryogenesis, and differentially induced by retinoic acid (RA) in human embryonal carcinoma (EC) NT2/D1 cells. We have sequenced 6.3 Kb of the genomic region containing the HOX-5.1 gene and analyzed its mechanisms of expression. Two alternative promoters underlie the transcription of two classes of HOX-5.1-specific mRNAs. These classes differ in tissue and subcellular distribution, induction by RA, structure of the 5'-UT region and mRNA stability: these features are compatible with a differential function of the two classes of transcripts in embryogenesis.

Amino Acid Sequence↗
PubMed1990

The three most downstream genes of the Hox-3 cluster are expressed in human extraembryonic tissues including trophoblast of androgenetic origin.

Human first trimester extraembryonic tissues of normal and androgenetic origin (molar pregnancies) were investigated for the expression of 6 homeobox genes from the chromosome 12-encoded Hox-3 cluster by non-autoradiographic in situ hybridization with biotinylated RNA probes. By comparative in situ hybridization involving the use of exon- or region-specific RNA probes, analysis included the cellular distribution of alternative Hox-3 transcripts in chorionic villous tissues. A bias in extraembryonic distribution was seen between transcripts of the three most upstream Hox-3 genes (Hox-3.7, -3.6, and -3.1) versus transcripts of the 3 most downstream genes (Hox-3.3, 3.4, and 3.5). Only genes from the latter group are transcribed in human extraembryonic tissues including extraembryonic tissues of androgenetic origin. Moreover, comparative in situ hybridization showed that distinct alternative transcripts of Hox-3.3, Hox 3.4 and Hox-3.5 are exclusively found in trophoblast cells while others are present in chorionic villous stromal cells as well. These data demonstrate the existence of tissue- and cell-specific use of transcriptional (alternative gene promoters) or post-transcriptional (alternative splicing) regulation of homeobox genes in extraembryonic tissues.

Chorionic Villi↗