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At least 487 records · Page 27Linked to original sources
PubMed1997

An upstream, DNase I hypersensitive region of the hematopoietic-expressed transcription factor GATA-1 gene confers developmental specificity in transgenic mice.

The transcription factor GATA-1, which is expressed in several hematopoietic lineages and multipotential progenitors, is required for the development of red blood cells and platelets. To identify control elements of the mouse GATA-1 gene, we analyzed DNase I hypersensitivity of the locus in erythroid chromatin and the expression of GATA-1/Escherichia coli beta-galactosidase (lacZ) transgenes in mice. Transgenes with 2.7 kb of promoter sequences are expressed infrequently and only within adult (definitive) erythroid cells. We show that inclusion of an upstream hypersensitive site (HS I) markedly enhances the frequency of expressing transgenic lines and activates expression in primitive erythroid cells. This pattern recapitulates the proper pattern of GATA-1 expression during development. By breeding a GATA-1/lacZ transgene into a GATA-1(-) background, we also have shown that the activation or maintenance of GATA-1 expression does not require the presence of GATA-1 itself, thereby excluding simple models of positive autoregulation. The transgene cassette reported here should be useful in directing expression of foreign sequences at the onset of hematopoiesis in the embryo and may assist in the identification of upstream regulators of the GATA-1 gene.

3T3 Cells↗
PubMed2003

A genomewide survey of developmentally relevant genes in Ciona intestinalis. III. Genes for Fox, ETS, nuclear receptors and NFkappaB.

A survey against the draft genome sequence and the cDNA/EST database of Ciona intestinalis identified a number of genes encoding transcription factors regulating a variety of processes including development. In the present study, we describe almost complete sets of genes for Fox, ETS-domain transcription factors, nuclear receptors, and NFkappaB as well as other factors regulating NFkappaB activity, with their phylogenetic nature. Vertebrate Fox transcription factors are currently delineated into 17 subfamilies: FoxA to FoxQ. The present survey yielded 29 genes of this family in the Ciona genome, 24 of which were Ciona orthologues of known Fox genes. In addition, we found 15 ETS genes, 17 nuclear receptor genes, and several NFkappaB signaling pathway genes in the Ciona genome. The number of Ciona genes in each family is much smaller than that of vertebrates, which represents a simplified feature of the ascidian genome. For example, humans have two NFkappaB genes, three Rel genes, and five NFAT genes, while Ciona has one gene for each family. The Ciona genome also contains smaller numbers of genes for the NFkappaB regulatory system, i.e. after the split of ascidians/vertebrates, vertebrates evolved a more complex NFkappaB system. The present results therefore provide molecular information for the investigation of complex developmental processes, and an insight into chordate evolution.

Animals↗
PubMed2005

Deletions involving long-range conserved nongenic sequences upstream and downstream of FOXL2 as a novel disease-causing mechanism in blepharophimosis syndrome.

The expression of a gene requires not only a normal coding sequence but also intact regulatory regions, which can be located at large distances from the target genes, as demonstrated for an increasing number of developmental genes. In previous mutation studies of the role of FOXL2 in blepharophimosis syndrome (BPES), we identified intragenic mutations in 70% of our patients. Three translocation breakpoints upstream of FOXL2 in patients with BPES suggested a position effect. Here, we identified novel microdeletions outside of FOXL2 in cases of sporadic and familial BPES. Specifically, four rearrangements, with an overlap of 126 kb, are located 230 kb upstream of FOXL2, telomeric to the reported translocation breakpoints. Moreover, the shortest region of deletion overlap (SRO) contains several conserved nongenic sequences (CNGs) harboring putative transcription-factor binding sites and representing potential long-range cis-regulatory elements. Interestingly, the human region orthologous to the 12-kb sequence deleted in the polled intersex syndrome in goat, which is an animal model for BPES, is contained in this SRO, providing evidence of human-goat conservation of FOXL2 expression and of the mutational mechanism. Surprisingly, in a fifth family with BPES, one rearrangement was found downstream of FOXL2. In addition, we report nine novel rearrangements encompassing FOXL2 that range from partial gene deletions to submicroscopic deletions. Overall, genomic rearrangements encompassing or outside of FOXL2 account for 16% of all molecular defects found in our families with BPES. In summary, this is the first report of extragenic deletions in BPES, providing further evidence of potential long-range cis-regulatory elements regulating FOXL2 expression. It contributes to the enlarging group of developmental diseases caused by defective distant regulation of gene expression. Finally, we demonstrate that CNGs are candidate regions for genomic rearrangements in developmental genes.

Animals↗
PubMed1990

Murine developmental control genes.

Various strategies have been used to isolate genes that participate in the regulation of mouse development. Gene families that have been identified on the basis of their homology to motifs within Drosophila control genes or human transcription factor genes, namely homeobox (Hox), paired-box (Pax), and POU genes, can be compared with respect to gene organization, structure, and expression patterns. The functions of these genes can be analyzed molecularly in vitro and in vivo with the use of available mouse mutants or transgenic mice. In addition, it has been possible to generate gain- or loss-of-function mutations by random or targeted introduction of transgenes. Models derived from these studies can reveal the successive steps of developmental control on a genetic level.

Animals↗
PubMed1988

The expression of rat homeobox-containing genes is developmentally regulated and tissue specific.

Seven rat homeobox-containing sequences have been isolated by screening a genomic library with a probe derived from a Drosophila antennapedia cDNA clone. The characterization of two of these homeobox-containing clones has been described (Falzon, M., Sanderson, N.D. and Chung, S. Y. (1987) Gene 54, 23-32). Sequence analysis of the remaining five homeobox regions reveals a 180 bp domain sharing 70-95% identity at the amino acid level with the homeodomain from the Drosophila antennapedia gene and with the homeodomains from other metazoan species. Genomic blot analysis shows that each of the homeobox-containing DNA segments is probably present in a single copy per haploid genome. Northern blot analysis of RNA transcripts indicates that the rat homeobox-containing sequences are expressed during embryogenesis and in newborn and adult tissues in a tissue-specific manner; RNA expression is predominantly detected in spinal cord and kidney. Moreover, the pattern of RNA transcripts observed is distinct for each homeobox sequence, indicating differential regulation. Among the seven rat homeobox-containing sequences, the flanking sequences of five of the clones have no obvious sequence similarity with previously published sequences of homeobox-containing genes from other species. Two of the rat clones have been identified as potential homologues to mouse homeobox-containing sequences. For both pairs, a high degree of amino acid conservation (greater than 95%) is observed within the homeodomain and its immediate flanking regions between the putative homologous genes in mouse and rat. This strengthens the assertion that some of the mammalian homeobox-containing genes encode highly conserved proteins and may serve important biological functions.

Amino Acid Sequence↗
PubMed1999

Molecular genetic analysis of the Drosophila trithorax-related gene which encodes a novel SET domain protein.

The products of the trithorax and Polycomb groups genes maintain the activity and silence, respectively, of many developmental genes including genes of the homeotic complexes. This transcriptional regulation is likely to involve modification of chromatin structure. Here, we report the cloning and characterization of a new gene, trithorax-related (trr), which shares sequence similarities with members of both the trithorax and Polycomb groups. The trr transcript is 9.6 kb in length and is present throughout development. The TRR protein, as predicted from the nucleotide sequence of the open reading frame, is 2431 amino acids in length and contains a PHD finger-like domain and a SET domain, two highly conserved protein motifs found in several trithorax and Polycomb group proteins, and in modifiers of position effect variegation. TRR is most similar in sequence to the human ALR protein, suggesting that trr is a Drosophila homologue of the ALR. TRR is also highly homologous to Drosophila TRITHORAX protein and to its human homologue, ALL-1/HRX. However, preliminary genetic analysis of a trr null allele suggests that TRR protein may not be involved in regulation of homeotic genes (i.e. not a member of the trithorax or Polycomb groups) or in position effect variegation.

Amino Acid Sequence↗
PubMed2003

Developmentally programmed gene elimination in Euplotes crassus facilitates a switch in the telomerase catalytic subunit.

The primary function of telomerase is to maintain preexisting telomere tracts. In the ciliate Euplotes crassus, however, telomerase RNP structure and substrate recognition are altered during macronuclear development to facilitate de novo telomere addition. We found that E. crassus harbors three TERT genes encoding the telomerase catalytic subunit that not only vary in their nucleotide and predicted protein sequences, but also in their expression profiles. Expression of EcTERT-1 and -3 correlates with the requirement for telomere maintenance, while that of EcTERT-2 correlates with de novo telomere synthesis. All three genes appear to require ribosomal frameshifting for expression of catalytically active protein. The transcriptionally active form of EcTERT-2 exists only transiently in mated cells and is absent from the vegetative macronucleus. Thus, telomerase expression in Euplotes is controlled by unique regulatory mechanisms that culminate in a developmental switch to a different catalytic subunit with properties suited to de novo telomere addition.

Amino Acid Sequence↗
PubMed1998

A developmentally regulated gene encoding a repressor-like protein is essential for sporulation in Streptomyces coelicolor A3(2).

whiH is one of several known loci specifically needed for the orderly multiple sporulation septation of aerial hyphae of Streptomyces coelicolor A3(2) and for the expression of at least some late sporulation genes. DNA complementing whiH mutants was located immediately upstream on hrdB, which encodes the principal sigma factor of S. coelicolor. Sequencing revealed a gene whose disruption gave rise to a typical whiH mutant phenotype. Four whiH mutants contained base changes or a frameshift in this gene. The deduced product of whiH related to a large family of bacterial regulatory proteins, the most similar being several repressors (such as GntR of Bacillus subtilis) responsive to carboxylate-containing intermediates in carbon metabolism. Transcription of whiH was initiated at a single promoter, PwhiH. Levels of whiH mRNA were developmentally regulated, increasing sharply when aerial mycelium was present, and reaching a maximum approximately when spores were first detectable. Transcript levels were markedly increased in a whiH mutant, indicating the possible involvement of WhiH in negative regulation of its own production. PwhiH was directly dependent on the sigma factor encoded by another sporulation gene, whiG, as shown by in vivo and in vitro transcription analysis.

Amino Acid Sequence↗
PubMed1989

A chicken homeo box gene with developmentally regulated expression.

Several homeo box sequences were isolated from a chicken (Gallus domesticus) genomic library. One phage, lambda GG7, was chosen for further study and the single homeo box sequence it contains was characterized. The sequence of the homeo box revealed it to be a distant member of the Antp class of homeo boxes. Expression of the CHox7 gene results in four transcripts, 1.4, 1.9, 2.4 and 3.5 kb in size. Transcript accumulation of the CHox7 gene peaks twice during embryogenesis, once with the 1.4 kb transcript during early somitogenesis and the second time with the 1.9 kb transcript during organogenesis.

Amino Acid Sequence↗
PubMed2005

The axon guidance receptor gene ROBO1 is a candidate gene for developmental dyslexia.

Dyslexia, or specific reading disability, is the most common learning disorder with a complex, partially genetic basis, but its biochemical mechanisms remain poorly understood. A locus on Chromosome 3, DYX5, has been linked to dyslexia in one large family and speech-sound disorder in a subset of small families. We found that the axon guidance receptor gene ROBO1, orthologous to the Drosophila roundabout gene, is disrupted by a chromosome translocation in a dyslexic individual. In a large pedigree with 21 dyslexic individuals genetically linked to a specific haplotype of ROBO1 (not found in any other chromosomes in our samples), the expression of ROBO1 from this haplotype was absent or attenuated in affected individuals. Sequencing of ROBO1 in apes revealed multiple coding differences, and the selection pressure was significantly different between the human, chimpanzee, and gorilla branch as compared to orangutan. We also identified novel exons and splice variants of ROBO1 that may explain the apparent phenotypic differences between human and mouse in heterozygous loss of ROBO1. We conclude that dyslexia may be caused by partial haplo-insufficiency for ROBO1 in rare families. Thus, our data suggest that a slight disturbance in neuronal axon crossing across the midline between brain hemispheres, dendrite guidance, or another function of ROBO1 may manifest as a specific reading disability in humans.

Alternative Splicing↗
PubMed2001

A dominant gene for developmental dyslexia on chromosome 3.

Developmental dyslexia is a neurofunctional disorder characterised by an unexpected difficulty in learning to read and write despite adequate intelligence, motivation, and education. Previous studies have suggested mostly quantitative susceptibility loci for dyslexia on chromosomes 1, 2, 6, and 15, but no genes have been identified yet. We studied a large pedigree, ascertained from 140 families considered, segregating pronounced dyslexia in an autosomal dominant fashion. Affected status and the subtype of dyslexia were determined by neuropsychological tests. A genome scan with 320 markers showed a novel dominant locus linked to dyslexia in the pericentromeric region of chromosome 3 with a multipoint lod score of 3.84. Nineteen out of 21 affected pedigree members shared this region identical by descent (corrected p<0.001). Previously implicated genomic regions showed no evidence for linkage. Sequencing of two positional candidate genes, 5HT1F and DRD3, did not support their role in dyslexia. The new locus on chromosome 3 is associated with deficits in all three essential components involved in the reading process, namely phonological awareness, rapid naming, and verbal short term memory.

Adolescent↗
PubMed1995

Flow cytometric study of differentiating cultures of Bacillus subtilis.

We report on 1) the development of a flow cytometry-based technique for detecting beta-galactosidase in differentiating cultures of Bacillus subtilis and 2) the application of this technique in the study of early developmental gene expression. The problems associated with generating detectable signals (despite the small size of B. subtilis cells) have been overcome using the fluorogenic substrate 5-octanolyaminofluorescein di-beta-D-galactopyranoside (C8-FDG). Additionally, to control for background fluorescence during the staining process, we included a control population in the C8-FDG staining mixture that consists of cells devoid of the lacZ gene prestained with another dye, PKH26. The distinct emission spectra of C8-fluorescein and PKH26 allow nonspecific C8-FDG staining in this control population to be monitored using two-color analysis. This technique has been applied in the study of developmental gene expression in sporulating cultures of B. subtilis, and it has been found that such cultures are heterogeneous, comprising two cell populations. One population is induced for expression of early sporulation genes, which is determined using lacZ fusions, whereas the other remains uninduced. These results have allowed us to understand better the patterns of gene expression exhibited by wild-type and mutant cultures early during the development process of spore formation.

Bacillus subtilis↗
PubMed1997

Postimplantation mouse embryos cultured in vitro. Assessment with whole-mount immunostaining and in situ hybridization.

The postimplantation embryos of rodents have been particularly convenient to study in culture using the whole embryo culture (WEC) system developed by New. Two serious limitations of the method will be illustrated in the present paper and proposals will be made to improve the quality of the information. The first limitation is that the developmental period amenable to culture has not been significantly extended in recent years. In the present paper, we show that the culture of mouse presomitic stages for 48 h leads to poorly reproducible results and frequent dysmorphogenic embryos. We also show that early somite stages cultured for 54 h or less have a normal growth and differentiation. In contrast, the culture of these embryos for 72 h results in subtle abnormalities of the head and the first branchial arch. The second limitation is that the gross morphology and histology are often not informative enough to distinguish between overall toxicity and developmental toxicity. We suggest some improvements by the association of WEC with two specific techniques: 1) whole-mount immunostaining of sensory ganglia and nerves and 2) in situ hybridization on histological sections using molecular probes for some developmental genes. Embryos reaching about the 30 somite stage at the end of the culture were processed for whole-mount immunostaining of sensory ganglia and nerves. We show that these structures are very sensitive to the noxious effects of HgCl2 and valproate. Both developmental retardations and dysmorphogeneses of the cervical ganglia and nerves were observed. Embryos were also exposed in vitro to low concentrations of all-trans-retinoic acid (AT-RA) and processed for in situ hybridization with radiolabeled anti-sense RNA probes for the Hoxb-1 and Hoxb-2 developmental genes. Three-dimensional reconstructions of the expression domains were performed. The data show that AT-RA induces ectopic expression domains of Hoxb-1. Our experiments demonstrate that techniques such as immunostaining and in situ hybridization can significantly expand the information obtained from whole postimplantation embryo culture.

Animals↗
PubMed2006

Role of sigmaD in regulating genes and signals during Myxococcus xanthus development.

Starvation-induced development of Myxococcus xanthus is an excellent model for biofilm formation because it involves cell-cell signaling to coordinate formation of multicellular mounds, gene expression, and cellular differentiation into spores. The role of sigma(D), an alternative sigma factor important for viability in stationary phase and for stress responses, was investigated during development by measuring signal production, gene expression, and sporulation of a sigD null mutant alone and upon codevelopment with wild-type cells or signaling mutants. The sigD mutant responded to starvation by inducing (p)ppGpp synthesis normally but was impaired for production of A-signal, an early cell density signal, and for production of the morphogenetic C-signal. Induction of early developmental genes was greatly reduced, and expression of those that depend on A-signal was not restored by codevelopment with wild-type cells, indicating that sigma(D) is needed for cellular responses to A-signal. Despite these early developmental defects, the sigD mutant responded to C-signal supplied by codeveloping wild-type cells by inducing a subset of late developmental genes. sigma(D) RNA polymerase is dispensable for transcription of this subset, but a distinct regulatory class, which includes genes essential for sporulation, requires sigma(D) RNA polymerase or a gene under its control, cell autonomously. The level of sigD transcript in a relA mutant during growth is much lower than in wild-type cells, suggesting that (p)ppGpp positively regulates sigD transcription in growing cells. The sigD transcript level drops in wild-type cells after 20 min of starvation and remains low after 40 min but rises in a relA mutant after 40 min, suggesting that (p)ppGpp negatively regulates sigD transcription early in development. We conclude that sigma(D) synthesized during growth occupies a position near the top of a regulatory hierarchy governing M. xanthus development, analogous to sigma factors that control biofilm formation of other bacteria.

Bacterial Proteins↗
PubMed2000

Characterization of a hemichordate fork head/HNF-3 gene expression.

Based on anatomical and developmental similarities, hemichordates are thought to be most closely related to chordates. However, so far very few developmental genes have been characterized from hemichordates. To gain molecular insight into the developmental mechanisms involved in the origin and evolution of chordates, we investigated the expression of a fork head/HNF-3 (PfHNF3) gene in the acorn worm embryo. Chordate fork head genes are implicated in the formation of endoderm, notochord and floor plate. We found that a PfHNF3 transcript was first detected at the early blastula stage; the signal of in situ hybridization was found in the vegetal plate cells, invaginating endoderm and then in the archenteron. By the late gastrula and into the early tornaria larva stages, an intense signal remained in the anterior region of the archenteron, while the expression in the other regions of archenteron decreased. The intense signal was retained in the pharynx of the tornaria larva. A comparison of the pattern of PfHNF3 with that of HNF-3 genes of sea urchin, ascidian, amphioxus and vertebrate suggests a possible acquisition of new functions of the gene during deuterostome evolution.

Amino Acid Sequence↗
PubMed1987

Expression of the proopiomelanocortin gene is developmentally regulated and affected by germ cells in the male mouse reproductive system.

Proopiomelanocortin (POMC), a major pituitary product, is also present in the adult mouse testis. We have shown previously that POMC mRNAs are most abundant in a subpopulation of Leydig cells associated with tubules in specific stages of the cycle of the seminiferous epithelium. In the present study, we examined the expression of the gene encoding POMC during testicular development and in other tissues of the male reproductive system. We also analyzed the effects of cellular interactions on POMC gene expression in the testis. Blot-hybridization analysis revealed that POMC transcripts of approximately equal to 800 nucleotides were present in enriched populations of meiotic prophase spermatocytes and in caput epididymis but were absent in cauda epididymis and vas deferens. POMC transcripts were present in fetal testis (day 17 of gestation to newborn), could not be detected in prepuberal testis (days 7-8 postpartum), but reappeared in the adult testis. No difference in the size or abundance of POMC transcripts was seen in testes from mouse mutant strains in which spermatogenesis is arrested in early spermiogenesis. In contrast, POMC transcripts were virtually undetectable in testes that are devoid of germ cells. These results emphasize the importance of interactions between germ cells and interstitial cells and the regulation of the POMC gene in the mammalian testis.

Animals↗
PubMed1991

Relationship between genotypes of longevity genes and developmental speed in Drosophila melanogaster.

Hatching time (the period between egg-laying and hatching) and emerging time were surveyed and their relationship with the adult life span was investigated. A relationship between emerging time and adult life span was clearly evident: early emergers were often long-lived. This relation is considered to have a genetic basis because all the larvae in a group were bred in the same culture bottle. Thus, the longevity genes involved also appear to have control over the rate of development. No significant relation was observed between hatching time and adult life span or between hatching time and emerging time. These results suggest that the function of the longevity genes begins at the larval or pupal stage before emergence, and that adult life spans differentiate at this time.

Animals↗