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P Gruss

Publications and source records attributed to P Gruss.

At least 163 records · Page 9Linked to original sources
PubMed1993

Mouse Oct-1 contains a composite homeodomain of human Oct-1 and Oct-2.

Members of the Oct family of transcription factors specifically interact with the octamer motif, ATGC-AAAT, a regulatory element important for tissue- and cell-specific transcription as well as for the expression of housekeeping genes. Except for Oct-1, all Oct factors are expressed in a temporally and spatially restricted mode during murine development and their number varies in a given cell type. Despite its ubiquitous expression pattern Oct-1 may play a role in murine development. As a first step towards elucidating the role of Oct-1 we report the complementary DNA cloning of the mouse Oct-1 gene. Two large transcripts of 5 and 14 kb are derived from a single gene. The expression patterns of three splicing products of Oct-1 are similar in a number of cells and tissues. In the POU region murine Oct-1 differs in four amino acids from the human homologue and these differences are restricted to helices 1 and 2. Interestingly, two of the four variant amino acids are identical to those in human and mouse Oct-2 and thus the murine Oct-1 homeodomain is intermediary in sequence between human Oct-1 and Oct-2. These two amino acids together with a third one have been shown to be relevant for the interaction between human Oct-1 and herpes simplex virus transactivator VP16. Nevertheless, VP16 interacts albeit weakly with murine Oct-1. We speculate that the differences in the human and mouse Oct-1 homeodomains reflect host-specific differences in protein-protein interactions.

Amino Acid Sequence↗
PubMed1993

The Antennapedia-type homeobox genes have evolved from three precursors separated early in metazoan evolution.

The developmental control genes containing an Antennapedia-type homeobox are clustered in insects and vertebrates. The evolution of these genes was studied by the construction of evolutionary trees and by statistical geometry in sequence space. The comparative analysis of the homeobox sequences reveals the subdivision of the Antennapedia-type homeobox genes into three classes early in metazoan evolution. This observation suggests an important function of these genes even in the most primitive metazoans. Subsequent duplication events generated a cluster of at least five homeobox genes in the last common ancestor of insects and vertebrates. These genes later independently gave rise to the 13 groups of paralogous genes in vertebrates and to the 11 Antennapedia-type genes in the Drosophila complexes.

Animals↗
PubMed1993

The oncogenic potential of Pax genes.

Our results demonstrate that murine paired domain-containing genes (Pax) can promote oncogenesis in tissue culture cells and in mice, and should thus be classified as a novel group of proto-oncogenes. The induction of tumor formation in mice was dependent on a functional paired domain, but did not require the presence of a homeodomain. Consequently, not only the Pax-3 and Pax-6 proteins, which in addition to paired domains contain intact homeodomains, but also Pax-2 and Pax-8, containing only residual homeodomains, and Pax-1, completely lacking a homeodomain, were able to induce transformation of cell cultures and tumor formation in mice. The oncogenic potential of the Pax proteins is dependent on the DNA binding function of the paired motif, as the Un-Pax-1 protein, which carries a point mutation in this domain that impairs DNA binding, is also defective in tumor formation. Therefore, the Pax gene products are not only involved in controlling embryogenesis, but they can, if deregulated, also induce tumorigenesis.

3T3 Cells↗
PubMed1993

Pax: gene regulators in the developing nervous system.

In recent years, the discovery of Pax genes in mouse has played an invaluable role in furthering our understanding in mouse developmental processes and disorders. To date, eight murine paired box-containing genes have been cloned. Seven of these exhibit a distinct spatiotemporal expression pattern in the developing nervous system implying a role in the regional specification of the developing spinal cord and brain. The Pax genes encode for sequence-specific DNA binding transcription factors that play a key role in embryonic development. Three of these developmental control genes are altered in mutant mice and two are associated with human diseases. Disruption of these Pax genes leads to abnormalities in neural crest derivatives, neuroectoderm, sclerotome or myotome-derived tissues. Disruption of the Pax-3 gene causes the Splotch phenotype in mice and Waardenburg syndrome in humans. Pax-6 mutations result in Small eye mice and the human genetic disorder aniridia. The Pax-1 gene is mutated in undulated mice. Pax proteins can transform cells in culture which then form tumours following injection in nude mice. Consistent with this activity, PAX3 has been recently implicated in the generation of the tumour alveolar rhabdomyosarcoma.

Animals↗
PubMed1993

The establishment of murine Hox-1 expression domains during patterning of the limb.

Region-specific expression patterns have been described recently for several candidate, developmental regulatory genes in the vertebrate limb. We have identified and mapped homeobox containing genes of the 5' part of the murine Hox-1 cluster by chromosomal walking. The expression of Hox-1.8, Hox-1.9, Hox-1.10, and a paralog of the Hox-4 cluster (Hox-4.5) were analyzed during stages when the developing limb pattern was being laid down. Each of these Hox genes was expressed in a restricted domain along the proximodistal axis of the limb at stage E 12.5. Only minor asymmetries were seen along the other two axes. A detailed spatiotemporal analysis of Hox expression, including three-dimensional reconstructions, revealed that the expression domains became progressively established between stages E 9.5 and E 12.5. Expression started from a small posterior and distal region and expanded toward the anterior part of the limb for 2 days. Depending on the gene and developmental stage, expression expands either along the ventral or the dorsal periphery. The establishment of the patterns was correlated to the growth process in the limb. Hox-1.8 and Hox-1.9 were also expressed in part of the somatopleure adjacent to the forelimb. The displacement of this domain toward the tip of the limb during development suggests that Hox-1.8 and Hox-1.9 were expressed in muscle precursor cells which migrate into the limb. The importance of these findings for the proposed models of limb pattern formation is discussed.

Amino Acid Sequence↗
PubMed1993

Neuronal expression of regulatory helix-loop-helix factor Id2 gene in mouse.

Id-like helix-loop-helix (HLH) proteins, which lack a basic DNA binding domain, have been suggested to serve as general inhibitors of differentiation. We present data that Id2 is expressed in specific cell types during neurogenesis and in the adult. At early stages of neurogenesis, Id2 is expressed in the ventricular zone of neuroepithelium. After the first neuronal populations are born, the expression of Id2 is down regulated in neuroepithelial cells and continues to be high in Purkinje cells of the cerebellum, in mitral cells of the olfactory bulb, and in layers 2, 3, and 5 of the cerebral cortex. In neuronally differentiating cell lines, the Id2 expression is up regulated (PCC7), down regulated (NG108), or unchanged (N18) during differentiation. Analyses of promoter sequences of the Id2 gene identify the region which is responsible for the down regulation of transcription during neuronal differentiation. Our data indicate that Id2 has different functions in different cell types during neurogenesis.

Animals↗
PubMed1993

Analysis of the Pax-3 gene in the mouse mutant splotch.

In a linkage analysis of Pax-3 and splotch no recombinations were found in 117 backcross mice. Molecular analysis of Pax-3 in three alleles of splotch shows a number of significant alterations to the Pax-3 gene. In Sp/Sp embryos, cDNA PCR analysis reveals a shortened transcript in which exon 4 of Pax-3 is deleted due to mutation of the splice acceptor site of intron 3. In the Sp4H allele, the Pax-3 gene is deleted and in Spd embryos, Pax-3 expression is significantly lower than that in normal littermate embryos. The linkage analysis, shortened Pax-3 transcript in Sp, and deletion of Pax-3 in Sp4H described here, together with the previous report of an intragenic deletion in Pax-3 in Sp2H mice and the deletion of Pax-3 in Spr mice, provide strong evidence for the allelic identity of Pax-3 and Sp.

Alleles↗
PubMed1993

Mapping of the human homologs of the murine paired-box-containing genes.

Mutations in paired-box-containing (Pax) genes have recently been found to be the primary lesions underlying human genetic disorders such as Waardenburg's Syndrome type 1 and mouse developmental mutants such as undulated (un), splotch (Sp), and small eye (Sey). In addition, PAX-6 is a strong candidate gene for aniridia in man. Eight independent Pax genes have been isolated in the mouse. All eight map to distinct regions of the mouse genome; they do not appear to be clustered in the same way as some groups of homeobox-containing genes. We have now mapped the human homologs of all eight of these genes; PAX genes are found on human Chromosomes (Chr) 1, 2, 7, 9, 10, 11, and 20.

Animals↗
PubMed1993

Cell type-specific negative regulatory element in low-affinity nerve growth factor receptor gene.

Developmental changes in the expression pattern of the low-affinity nerve growth factor receptor (LNGFR) gene suggest a complex mechanism of gene regulation. We demonstrate the presence of a negative regulatory element (NRE) localized to a 40 base pair (bp) segment, -1731 to -1690 bp upstream from the translation start site in the LNGFR gene. The NRE possesses two tandemly arranged sequences with similarity to immunoglobulin gene enhancer E-boxes. The NRE is active in neurons and neuronal cell lines but not in astrocytes. Electrophoretic mobility shift analysis (EMSA) demonstrates changing expression pattern of proteins binding to the NRE in developing nervous system. Since the specific binding of the proteins to the NRE is competed with oligonucleotides containing E-box sequences we suggest that factor(s) responsible for down regulation of LNGFR gene include members of the helix-loop-helix class of transcription factors.

Animals↗
PubMed1993

Prox 1, a prospero-related homeobox gene expressed during mouse development.

Prox 1, a likely mouse homologue of the Drosophila homeobox gene prospero has been cloned and its expression pattern analyzed during development. In Drosophila, prospero is expressed in the developing CNS, lens-secreting cone cells of the eye, and midgut. In the mouse, Prox 1 is expressed in many of the same tissues: young neurons of the subventricular region of the CNS, developing eye lens and pancreas. Expression is also detected in the developing liver and heart, as well as transiently in the skeletal muscles. The similarities in protein sequence and expression patterns between the mouse and fly cognate genes suggest that Prox 1 may play, among others, a fundamental role in early development of the murine CNS.

Amino Acid Sequence↗
PubMed1993

Altered Pax gene expression in murine notochord mutants: the notochord is required to initiate and maintain ventral identity in the somite.

We have characterised the patterning capacity of the notochord on the somite using the murine Pax-1 gene as a ventral, and Pax-3 as a dorsal molecular marker. As model systems we chose the four mouse notochord mutants Brachyury curtailed (Tc), Danforth's short tail (Sd), Pintail (Pt) and truncate (tc). Their notochord either is initially absent or progressively degenerates. The use of these mutants enabled us to compare the effect of graded notochord deficiencies. All four mutants show premature termination of the vertebral column. This phenotype can be traced back to an impaired dorsoventral specification of the somites. In tc/tc and Tc/+ embryos the notochord in the affected regions is missing from the beginning. Consequently, Pax-1 is never activated, and Pax-3 remains to be expressed in the entire somite. In contrast, in Sd and Pt embryos the notochord secondarily degenerates. At the end of the prevertebral column Pax-1 expression is lost, while the Pax-3 signal occupies the former Pax-1 expressing zone. The altered pax gene expression in the notochord mutants suggests that the notochord is required for two processes in the dorsoventral patterning of the somite: first the induction of ventral structures, and second the maintenance of the ventral fate.

Animals↗
PubMed1993

Mutations in the PAX3 gene causing Waardenburg syndrome type 1 and type 2.

Waardenburg syndrome (WS) is a combination of deafness and pigmentary disturbances, normally inherited as an autosomal dominant trait. The pathology involves neural crest derivatives, but WS is heterogeneous clinically and genetically. Some type I WS families show linkage with markers on distal 2q and in three cases the disease has been attributed to mutations in the PAX3 gene. PAX3 encodes a paired domain, a highly conserved octapeptide and probably also a paired-type homeodomain. Here we describe a further three PAX3 mutations which cause WS; one alters the octapeptide motif plus the presumed homeodomain; a second alters all three elements and the third alters the paired box alone. The latter occurs in a family with probable type 2 WS, a clinical variant usually considered not to be allelic with type 1 WS.

Amino Acid Sequence↗
PubMed1993

Murine Pax-2 protein is a sequence-specific trans-activator with expression in the genital system.

The murine paired box containing gene Pax-2 has been proposed to be involved in kidney and central nervous system (CNS) development. In this report, we show that expression cloning of Pax-2 cDNA allowed in vitro identification of specifically bound DNA sequences. When fused to the thymidine kinase (TK) promoter in front of reporter genes, these target sequences were able to mediate trans-activation by Pax-2 protein, thus demonstrating their in vivo function. Expression studies from adult mouse tissues revealed high levels of Pax-2 transcripts in male and female genital tracts, suggesting a second phase of Pax-2 activity. Sequence-specific DNA binding and subsequent modulation of promoter activities may constitute the molecular mechanism of Pax-2 action in specific adult tissues and during development.

Animals↗
PubMed1993

Mouse Cdx-1 expression during gastrulation.

We describe the expression pattern of the mouse Cdx-1 gene during early development, examined by both RNA and protein analyses. Cdx-1 expression began with the onset of the head process formation (day 7.5) in ectodermal and mesodermal cells of the primitive streak. Expression extended initially to the middle of the prospective hindbrain and subsequently regressed caudad to the spinal cord level by day 9.5. The mesoderm-specific expression was detected in the first somites and could be followed during their differentiation to the myotome of the dorsal somitic edge by day 12. The developing limb buds and the mesonephros exhibited expression up to day 12. No signal could be detected in notochordal cells and cells of the definitive endoderm. Thus, Cdx-1 is expressed during gastrulation when anterior-posterior positional values are established along the embryonic axes. Furthermore, the expression correlates with the formation of segmented tissue in the posterior hindbrain, the spinal cord and structures like the mesonephros.

Animals↗
PubMed1993

Signals from the notochord and floor plate regulate the region-specific expression of two Pax genes in the developing spinal cord.

Members of the paired box (Pax) gene family are expressed in discrete regions of the developing central nervous system, suggesting a role in neural patterning. In this study, we describe the isolation of the chicken homologues of Pax-3 and Pax-6. Both genes are very highly conserved and share extensive homology with the mouse Pax-3 and Pax-6 genes. Pax-3 is expressed in the primitive streak and in two bands of cells at the lateral extremity of the neural plate. In the spinal cord, Pax-6 is expressed later than Pax-3 with the first detectable expression preceding closure of the neural tube. When the neural tube closes, transcripts of both genes become dorsoventrally restricted in the undifferentiated mitotic neuroepithelium. We show that the removal of the notochord, or implantation of an additional notochord, dramatically alter the dorsoventral (DV) expression patterns of Pax-3 and Pax-6. These manipulations suggest that signals from the notochord and floor plate regulate the establishment of the dorsoventrally restricted expression domains of Pax-3 and Pax-6 in the spinal cord. The rapid changes to Pax gene expression that occur in neural progenitor cells following the grafting of an ectopic notochord suggest that changes to Pax gene expression are an early effect of the notochord on spinal cord patterning.

Amino Acid Sequence↗
PubMed1993

The oncogenic potential of deregulated homeobox genes.

Homeobox genes encode DNA-binding proteins that regulate gene expression during embryonic development. Deregulation of homeobox gene expression has been invoked as the molecular basis of a number of leukemias. We now demonstrate, using in vitro and in vivo transformation assays, that the overexpression of homeobox genes is the basis for transformation and tumorigenesis. Thus, clustered homeobox genes related to Drosophila Hom genes (Hoxa-7, Hoxa-5, Hoxa-1, Hoxb-7, and Hoxc-8) as well as the homeobox genes Evx-1 and Cdx-1 constitute a new family of nuclear protooncogenes. This finding suggests that many homeobox genes regulating embryogenesis can--if deregulated--also contribute to tumorigenesis.

Animals↗
PubMed1993

[The traumatic origin of a glioblastoma].

A 56-year-old man is reported who had suffered a frontal, frontobasal open craniocerebral injury four years ago. He presented for treatment with a glioblastoma of which the location and extent precisely corresponded to that of the prior brain injury. After surgical exposure of the tumor, we had the impression that the tumor initially showed granulating growth from the frontal injury site and had then given rise to more highly vascularized and also necrotizing tumor tissue spreading into the frontal medullary layer with typical glioblastoma characteristics. In view of the surgical site, it is logical to consider a tumorigenesis after cerebral trauma, which is also corroborated by the histological results, since more proliferative tumor growth was found near to the injury and more highly vascularized but also necrotizing (i.e. more typical of a glioblastoma) tumor growth far away from the injury. After the comparison of our observation with the corresponding cases in the literature, it is shown that there is at least in part a causal correlation between the trauma and tumorigenesis: in the previously healthy patient, the tumor developed precisely in the region of the injury (with detection of destroyed brain tissue) after a sufficiently long time interval. Near to the site of damage, it showed granulative growth with a low degree of vascularization, and then passed into the typical glioblastoma. Observations of genetic changes in glioblastoma patients is not inconsistent with this possible trauma genesis, but render it probable that trauma is the factor which can give rise to tumor growth in a corresponding susceptibility to tumorigenesis.

Brain Neoplasms↗