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Biomedical subjects

E Boncinelli

Publications and source records attributed to E Boncinelli.

At least 55 records · Page 3Linked to original sources
PubMed1997

Evolution of Emx genes and brain development in vertebrates.

Emx1 and Emx2 genes are known to be involved in mammalian forebrain development. In order to investigate the evolution of the Emx gene family in vertebrates, a phylogenetic analysis was carried out on the Emx genes sequenced in man, mice, frogs, coelacanths and zebrafish. The results demonstrated the existence of two clades (Emx1 and Emx2), each grouping one of the two genes of the investigated taxa. The only exception was the zebrafish Emx1-like gene which turned out to be a sister group to both the Emx1 and Emx2 clusters. Such striking sequence divergence observed for the zebrafish Emx1-like gene could indicate that it is not orthologous to the other Emx1 genes, and therefore, in vertebrates there must be three Emx genes. Alternatively, if the zebrafish emx1 gene is orthologous to the tetrapod one, it must have undergone to strong diversifying selection.

Animals↗
PubMed1997

Anf: a novel class of vertebrate homeobox genes expressed at the anterior end of the main embryonic axis.

Five novel genes homologous to the homeobox-containing genes Xanf-1 and Xanf-2 of Xenopus and Hesx-1/Rpx of mouse have been identified as a result of a PCR survey of cDNA in sturgeon, zebrafish, newt, chicken and human. Comparative analysis of the homeodomain primary structure of these genes revealed that they belong to a novel class of homeobox genes, which we name Anf. All genes of this class investigated so far have similar patterns of expression during early embryogenesis, characterized by maximal transcript levels being present at the anterior extremity of the main embryonic body axis. The data obtained also suggest that, despite considerable high structural divergence between their homeodomains, all known Anf genes may be orthologues, and thus represent one of the most quickly evolving classes of vertebrate homeobox genes.

Amino Acid Sequence↗
PubMed1997

Implication of OTX2 in pigment epithelium determination and neural retina differentiation.

The expression pattern of Otx2, a homeobox-containing gene, was analyzed from the beginning of eye morphogenesis until neural retina differentiation in chick embryos. Early on, Otx2 expression was diffuse throughout the optic vesicles but became restricted to their dorsal part when the vesicles contacted the surface ectoderm. As the optic cup forms, Otx2 was expressed only in the outer layer, which gives rise to the pigment epithelium. This early Otx2 expression pattern was complementary to that of PAX2, which localizes to the ventral half of the developing eye and optic stalk. Otx2 expression was always observed in the pigment epithelium at all stages analyzed but was extended to scattered cells located in the central portion of the neural retina around stage 22. The number of cells expressing Otx2 transcripts increased with time, following a central to peripheral gradient. Bromodeoxyuridine labeling in combination with immunohistochemistry with anti-OTX2 antiserum and different cell-specific markers were used to determine that OTX2-positive cells are postmitotic neuroblasts undergoing differentiation into several, if not all, of the distinct cell types present in the chick retina. These data indicate that Otx2 might have a double role in eye development. First, it might be necessary for the early specification and subsequent functioning of the pigment epithelium. Later, OTX2 expression might be involved in retina neurogenesis, defining a differentiation feature common to the distinct retinal cell classes.

Animals↗
PubMed1997

Branchial HOX gene expression and human craniofacial development.

Members of the Antennapedia class of homeobox genes, known as Hox genes, are believed to be pivotal in vertebrate craniofacial development. Here we show that eight members of paralogous groups 1, 2, 3, and 4 are expressed in the human embryonic hindbrain and branchial arches at 4 weeks of development. The combinatorial patterns of expression of genes representing the first three paralogous groups parallel the patterns described for their homologues in various animal models, demonstrating a high degree of conservation of the branchial Hox code. Arch expression of group 4 genes is defined for the first time in any vertebrate. Furthermore, as development proceeds, individual paralogues of a single paralogous group (group 3), which initially share a common expression domain, are differentially down-regulated in a tissue-, organ-, or site-specific fashion.

Branchial Region↗
PubMed1997

Transcription factors and head formation in vertebrates.

Evidence from Drosophila and also vertebrates predicts that two different sets of instructions may determine the development of the rostral and caudal parts of the body. This implies different cellular and inductive processes during gastrulation, whose genetic requirements remain to be understood. To date, four genes encoding transcription factors expressed in the presumptive vertebrate head during gastrulation have been studied at the functional level: Lim-1, Otx-2, HNF-3 beta and goosecoid. We discuss here the potential functions of these genes in the formation of rostral head as compared to posterior head and trunk, and in the light of recent fate map and expression analyses in mouse, chick, Xenopus and zebrafish. These data indicate that Lim-1, Otx-2 and HNF-3 beta may be involved in the same genetic pathway controlling the formation of the prechordal mesendoderm, which is subsequently required for rostral head development. goosecoid may act in a parallel pathway, possibly in conjunction with other, yet unidentified, factors.

Animals↗
PubMed1997

Inactivation of the zebrafish homologue of Chx10 by antisense oligonucleotides causes eye malformations similar to the ocular retardation phenotype.

We report the cloning of a zebrafish paired-type homeobox gene, Alx, closely related to the murine Chx10 and the gold fish Vsx-I homeodomain proteins. Alx is first expressed at about 12 h post-fertilization (hpf) when optic vesicles appear. Its expression is restricted to the early retinal neuroepithelium, whereas no signal can be detected in the optic placode. Later, Alx expression follows the differentiation of the neural retina. Inhibition experiments with antisense oligonucleotides resulted in specific eye malformations which are reminiscent of the phenotype of ocular retardation (or) mice, caused by a spontaneous Chx10 mutation. The expression of other developmentally relevant genes such as pax(zf-a), pax(zf-b) and krx-20 was not affected in the antisense treated embryos.

Amino Acid Sequence↗
PubMed1997

Homeobox genes and disease.

To date, not many disorders have been associated with homeobox genes, especially with those belonging to the HOX family. This is particularly surprising, considering the body of evidence accumulated for a role of these genes in the control of mammalian development. Recently, this situation has changed and some congenital or somatic defects have been demonstrated to involve mutations in homeobox genes of the HOX, EMX, PAX, and MSX families, as well as in other novel genes containing either a paired- or bicoid-type homeobox.

Animals↗
PubMed1997

The human homeodomain protein OTX2 binds to the human tenascin-C promoter and trans-represses its activity in transfected cells.

Homeodomain-containing proteins mediate many transcriptional processes in eukaryotes during development. Recently, mammalian homeodomain proteins involved in the anterior head formation have been discovered, but their effect on gene transcription has never been investigated. Here we report on the ability of the human homeodomain protein OTX2 to bind with high affinity to a target sequence present in the promoter of the gene encoding the human extracellular matrix protein tenascin-C and to repress its transcriptional activity in transiently transfected cells.

Animals↗
PubMed1997

Familial schizencephaly associated with EMX2 mutation.

We describe two brothers aged 8 and 10 affected by severe bilateral schizencephaly, carrying an identical point mutation of the homeobox gene EMX2. Both children had severe neurologic deficits and mental retardation, although they differed in the anatomic extent of the brain malformation and in the severity of the clinical picture. The present findings, together with the reported cases of schizencephaly associated with EMX2 mutations, support the hypothesis that, at least in some cases, schizencephalies are determined by deleterious mutations of this homeobox gene. The different morphoclinical pictures suggest that, besides the EMX2 mutation, other factors are relevant in determining the severity of the brain malformation and clinical picture.

Brain↗
PubMed1997

Activating and repressing signals in head development: the role of Xotx1 and Xotx2.

Xotx1 and Xotx2 are two Xenopus homologues of the Drosophila orthodenticle gene that are specifically expressed in presumptive head regions that do not undergo convergent extension movements during gastrulation. We studied the function of Xotx1 and compared it with that of Xotx2. Ectopic expression of each of the two genes has similar effects in impairing trunk and tail development. Experimental evidence suggests that posterior deficiencies observed in microinjected embryos are due to negative interference with convergent extension movements. Transplantations of putative tail-forming regions showed that, while Xotx1 overexpression inhibits tail organizer activity, Xotx2 overexpression is able to turn a tail organizer into a head organizer. Finally, Xotx1 and Xotx2 are activated by factors involved in head formation and repressed by a posteriorizing signal like retinoic acid. Taken together, these data suggest that Xotx genes are involved in head-organizing activity. They also suggest that the head organizer may act not only stimulating the formation of anterior regions, but also repressing the formation of posterior structures.

Animals↗
PubMed1996

cDNA sequence, map, and expression of the murine homolog of GTBP, a DNA mismatch repair gene.

DNA mismatch repair genes (MMR) have been actively studied in humans for their role in cancer susceptibility. Recently, GTBP, a new member of the MMR gene family, has been cloned and found to encode a 160-kDa protein that forms a heterodimer with hMSH2. Our group has isolated and characterized the mouse homolog of GTBP. The transcript, termed Gtmbp (G/T mismatch-binding protein), encodes a protein highly similar to its human counterpart. The gene is markedly conserved across species and maps to the distal portion of mouse chromosome 17, in a region homologous to human 2p. One Gtmbp-related sequence maps to proximal mouse chromosome 4. Studies of the expression of Gtmbp suggest that its regulated transcription is tightly linked to the level of DNA replication, consistent with the protein's DNA proofreading function.

Animals↗
PubMed1996

Expression of HOXC4, HOXC5, and HOXC6 in human lymphoid cell lines, leukemias, and benign and malignant lymphoid tissue.

Besides their regulatory role in embryogenesis, homeobox (HOX) genes are expressed in a specific manner in hematopoietic cell lineages, implying a role in the molecular regulation of hematopoiesis. Some HOX C cluster genes are found to be expressed in lymphoid cells of mice and humans. Their function and expression in normal hematopoiesis are still largely unknown. We have studied the mRNA expression of HOXC4, HOXC5, and HOXC6 in several stages of lymphocyte maturation by reverse transcriptase-polymerase chain reaction (RT-PCR) and RNA in situ hybridization (RISH). We examined CD34+/CD38low and CD34+/CD38high cells obtained from normal donor bone marrow (BM), a panel of 19 lymphoid cell lines, several types of leukemias and non-Hodgkin's lymphomas (NHL), and lymphocytes isolated from tonsillar tissue and peripheral blood (PB). HOXC4 and HOXC6 were found to be expressed during maturation in B- and T-lymphoid cells. The expression of each gene was found to be initiated at different cell maturation stages. HOXC4 transcripts were present in CD34+/CD38low cells, which are thought to comprise stem cells and noncommitted progenitor cells, and in subsequent stages to terminally maturated lymphoid cells. HOXC6 expression is initiated in equivalents of prothymocyte and pre-pre-B cell stage and remains present in mature cells. However, HOXC5 is only expressed in neoplastic cell lines and in neoplastic cells of NHL, but not in CD34+ BM cells, nor in resting or activated lymphoid cells isolated from tonsil, PB, or in leukemia cells. In cell lines, weak expression of HOXC5 is initiated in equivalents of pre-B cell and common thymocyte stage and is continuously expressed in mature cell lines. Semi-quantitative RT-PCR showed that expression levels of HOXC5 were much lower than those of HOXC4 and HOXC6; furthermore an increase of expression of HOXC4, HOXC5, and HOXC6 during lymphoid cell differentiation was demonstrated. Thus, mainly mature lymphoid cell lines and neoplastic cells of NHL do express HOXC5, in contrast to the lack of expression in normal lymphoid cells and leukemias. These findings suggest involvement of HOXC5 in lymphomagenesis.

Base Sequence↗
PubMed1996

Xotx genes in the developing brain of Xenopus laevis.

The vertebrate Otx gene family is related to otd, a gene contributing to head development in Drosophila. We previously reported on the expression of Xotx2 gene, homologous to the murine Otx2 gene, during early Xenopus development. In the present paper we report an extensive analysis of the expression pattern of Xotx2 during later stages of development and also the cloning and developmental expression of two additional Otx Xenopus genes, Xotx1 and Xotx4. These latter two genes bear a good degree of homology to murine Otx1, higher for Xotx1 than for Xotx4. Both these genes are expressed in the forebrain and midbrain regions and their developmental patterns of expression are very similar, although not perfectly superimposable. Spatial and temporal expression patterns of the three Xotx genes suggest that they may be involved in the early subdivision of the rostral brain, providing antero-posterior positional information within the most anterior districts of the neuraxis. The three Xotx genes are expressed in all the developing sense organs of the head, eyes, olfactory system and otic vesicles. By in situ hybridization the earliest detectable expression is found in anterior mesendoderm for Xotx2, and in presumptive anterior neuroectoderm for Xotx1 and Xotx4. In addition, we examined whether Xotx1 is expressed in exogastrulae, finding that Xotx1 expression can be activated in the apparent absence of vertical signals of neural induction.

Amino Acid Sequence↗
PubMed1996

EMX1 homeoprotein is expressed in cell nuclei of the developing cerebral cortex and in the axons of the olfactory sensory neurons.

We analyzed the distribution of EMX1 during mouse development. EMX1 is a homeoprotein encoded by Emx1, a regulatory homeobox gene expressed in the developing forebrain. Its distribution essentially overlaps the expression domains of Emx1 transcripts. The EMX1 protein is present in the developing dorsa telencephalon, that is in the cerebral cortex, olfactory bulb and hippocampus. In the cerebral cortex EMX1 is present in nuclei of proliferating, differentiating and most mature neurons belonging to all cortical layers. In the olfactory bulb it is present in all proliferating cells during development, whereas postnatally it is faintly expressed in some mitral cells. Non-cerebral localizations include a transient expression in branchial pouches, in the apical ectodermal ridge of the developing limbs and in the developing kidney. Of particular interest is the presence of EMX1 in the olfactory nerve from its first appearance during embryogenesis to birth. The protein is present in axons of olfactory sensory neurons along their entire length, including their terminals in spherical regions of neuropil in the olfactory bulb called glomeruli.

Animals↗
PubMed1996

OTX2 homeoprotein in the developing central nervous system and migratory cells of the olfactory area.

We analyzed the distribution of OTX2 during mouse development. OTX2 is a homeoprotein encoded by Otx2, a vertebrate homeobox gene expressed in the developing brain and anterior head regions. The protein is already detectable in pre-streak embryos, in nuclei of embryonic ectoderm or epiblast and primitive endoderm or hypoblast. Its distribution is uniform along the entire epiblast, while showing an antero-posterior gradient along the hypoblast at the time when primitive streak first forms. Between embryonic day 7 (E7) and E7.5 there is a progressive confinement of the protein to the anterior ectoderm corresponding to the forming headfold. At E7.5-E7.8, the protein is mainly confined in this region but is still present, though at lower level, in more posterior ectoderm. Starting from day 8 of development it is essentially confined to anterior neuroectoderm corresponding to presumptive fore- and midbrain. Its subsequent distribution in forebrain, midbrain, developing isthmo-cerebellum and posterior central nervous system is analyzed in detail. Of particular interest is the presence of OTX2 in nuclei of cells of the olfactory system starting from its origin in the olfactory placode. OTX2 protein is present in some cells of the olfactory epithelium, in both the major olfactory epithelium and the vomero-nasal organ, and in scattered migratory cells present in the mesenchyme outside it. These cells surround the axon bundles of the olfactory nerve along its path from the olfactory epithelium in the nasal cavities to the olfactory bulb in rostral telencephalon and include both ensheathing glial cells and luteinizing hormone-releasing hormone (LHRH)-positive cells.

Age Factors↗
PubMed1996

Schizencephaly: surgical features and new molecular genetic results.

Schizencephaly is a rare developmental disorder characterized by a full thickness cleft within the cerebral hemispheres. Large portions of the cerebral hemispheres may be missing and are replaced by cerebrospinal fluid (CSF). The walls of the clefts are lined by polymicrogyric grey matter and are covered by the so-called "pialependymal seam". The cleft may be unilateral or bilateral, and if bilateral are fairly symmetrical. Their dimensions can be small or large. The clinical features may vary from a normal to a severe development delay. 13 patients with this anomaly have been evaluated. Using SSCP (single strand conformation polymorphism) analysis, as previously described (2), they were found to have a mutant homeobox gene, Emx2.

Abnormalities, Multiple↗