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PubMedDate not supplied

Functional analysis of Drosophila developmental genes instrumental in tumor suppression.

Of the 28 presently known Drosophila tumor suppressor genes we present the status of the functional analysis of the following three genes: (a) lethal (3) malignant brain tumor [1(3)mbt], which by homology belongs to the Pc-G gene family and may be involved in the stable silencing of specific developmental genes by changing the chromatin structure, and thus establishing and maintaining the differentiated state; (b) lethal (3) malignant blood neoplasm-1 [1(3)mbn-1], for whose function only vague predictions can be made; 4) benign (2) gonial cell neoplasm [b(2)gcn], which may function as a splice factor. Each Drosophila tumor suppressor gene transforms in the homozygously mutated state either one or two specific cell-types in a single step, and is thus the primary cause for tumorigenesis. For one of the genes a putative human homologue has been found.

Animals↗

PubMed1998

Ocular malformations and developmental genes.

New insights into the pathogenesis of ocular malformations came with the discovery of transcription factors that determine the fate of cells in the developing eye. Several malformations have been matched to individual developmental genes that share conserved DNA sequences such as the homeobox. These disease/gene matches include the oculorenal syndrome and PAX2; aniridia and PAX6; Rieger syndrome and RIEG1/PITX2; cyclopia and Sonic hedgehog; cone-rod dystrophy, Leber's congenital amaurosis and CRX; and recessive septooptic dysplasia and HESX1. Gene mapping and mutation analysis have allowed a more accurate and meaningful classification of genetically heterogeneous diseases such as the anterior segment dysgenesis syndromes. This paper reviews current information on the genetics of ocular malformations.

Eye Abnormalities↗

PubMed1996

The Drosophila developmental gene fat facets has a human homologue in Xp11.4 which escapes X-inactivation and has related sequences on Yq11.2.

EST 221 derived from human adult testis detects homology to the Drosophila fat facets gene (fat) and has related sequences on both the X and Y chromosomes mapping to Xp11.4 and Yq11.2 respectively. These two loci have been termed DFFRX and DFFRY for Drosophila fat facets related X and Y. The major transcript detected by EST 221 is-8 kb in size and is expressed widely in a range of 16 human adult tissues. RT-PCR analysis of 13 different human embryonic tissues with primers specific for the X and Y sequences demonstrates that both loci are expressed in developing tissues and quantitative RT-PCR of lymphoblastoid cell lines carrying different numbers of X chromosomes reveals that the X-linked gene escapes X-inactivation. The amino acid sequence (2547 residues) of the complete open reading frame of the X gene has 44% identity and 88% similarity to the Drosophila sequence and contains the conserved Cys and His domains characteristic of deubiquitinating enzymes, suggesting its biochemical function may be the hydrolysis of ubiquitin from protein-ubiquitin conjugates. The requirement of faf for normal oocyte development in Drosophila combined with the map location and escape from X-inactivation of DFFRX raises the possibility that the human homologue plays a role in the defects of oocyte proliferation and subsequent gonadal degeneration found in Turner syndrome.

Adult↗

PubMed2005

Finding the center reliably: robust patterns of developmental gene expression.

We investigate a mechanism for the robust identification of the center of a developing biological system. We assume the existence of two morphogen gradients, an activator emanating from the anterior, and a corepressor from the posterior. The corepressor inhibits the action of the activator in switching on target genes. We apply this system to Drosophila embryos, where we predict the existence of a hitherto undetected posterior corepressor. Using mathematical modeling, we show that a symmetric activator-corepressor model can quantitatively explain the precise midembryo expression boundary of the hunchback gene, and the scaling of this pattern with embryo size.

Animals↗

PubMed2005

Neonatal antibiotic treatment alters gastrointestinal tract developmental gene expression and intestinal barrier transcriptome.

The postnatal maturation of the gut, partially modulated by bacterial colonization, ends up in the establishment of an efficient barrier to luminal antigens and bacteria. The use of broad-spectrum antibiotics in pediatric practices alters the gut bacterial colonization and, consequently, may impair the maturation of the gut barrier function. To test this hypothesis, suckling Sprague-Dawley rats received a daily intragastric gavage of antibiotic (Clamoxyl; an amoxicillin-based commercial preparation) or saline solution from postnatal day 7 (d7) until d17 or d21. Luminal microbiota composition and global gene expression profile were analyzed on samples from small intestine and colon of each group. The treatment with Clamoxyl resulted in the almost-complete eradication of Lactobacillus in the whole intestine and in a drastic reduction of colonic total aerobic and anaerobic bacteria, in particular Enterobacteriacae and Enterococcus. The global gene expression analysis revealed that Clamoxyl affects the maturation process of 249 and 149 Affymetrix probe sets in the proximal and distal small intestine, respectively, and 163 probe sets in the colon. The expression of genes coding for Paneth cell products (defensins, matrilysin, and phospholipase A2) was significantly downregulated by the Clamoxyl treatment. A significant downregulation of major histocompatibility complex (MHC) class Ib and II genes, involved in antigen presentation, was also observed. Conversely, mast cell proteases expression was upregulated. These results suggest that early treatment with a large-spectrum antibiotic deeply affects the gut barrier function at the suckling-weaning interface, a period during which the gut is challenged by an array of novel food-borne antigens.

Aging↗

PubMed1995

A network model of developmental gene hierarchy.

A network model of development governing the whole temporal and spatial hierarchy of early embryogenesis and pattern formation in Drosophila is introduced. The network is related to a neural network model, with its units being developmental genes mostly connected by the genes' DNA-binding products. The developmental network's agreement with predictions regarding architecture and function of the neural network provides adequate grounds for an analogy between the two. The model is tested through computer simulations--predictions compare favorably with experimental observations. The model not only incorporates a program of control at gene level, but also makes a direct connection with current molecular studies throughout the whole hierarchy of the early embryogenesis of Drosophila.

Animals↗

PubMed2006

Molecular characterization of the developmental gene in eyes: through data-mining on integrated transcriptome databases.

OBJECTIVES: Our aim was to utilize publicly available and proprietary sources to discover candidate genes important for ocular development. DESIGN AND METHODS: The collated information on our 5092 non-redundant clusters was grouped and functional annotation was conducted using gene ontology (FatiGO) for categorizing them with respect to molecular function. The web-based viewer technological platform (H-InvDB) was employed for transcription analyses of in-house high quality fetal eye Expressed Sequence Tags (ESTs). Eye-specific ESTs were also analyzed across species by using EMBEST. RESULTS: According to adult eye cDNA libraries, nucleic acid binding and cell structure/cytoskeletal protein genes were the most abundant among the ESTs of fetal eyes. Using cDNA assembly in H-InvDB, 20 (80%) of the 25 most commonly expressed genes in the human eye are also expressed in extraocular tissues. The crystalline gamma S gene is highly expressed in the eye, but not in other tissues. We used EMBEST to compare human fetal eye and octopus eye ESTs and the expression similarity was low (1.6%). This indicated that our fetal eye library contains genes necessary for the developmental process and biological function of the eye, which may not be expressed in the fully developed octopus eyes. The human fetal eye cDNA library also contained highly abundant eye tissue genes, including alphaA-crystallin, eukaryotic translation elongation factor 1 alpha 1 (EEF1A1), bestrophin (VMD2), cystatin C, and transforming growth factor, beta-induced (BIGH3). CONCLUSIONS: Our annotated EST set provides a valuable resource for gene discovery and functional genomic analysis. This display will help to appreciate the strengths and weaknesses of the different technological platforms, so that in future studies the maximum amount of beneficial information can be derived from the appropriate use of each method.

Animals↗

PubMed2005

Developmental gene expression of lactoferrin and effect of dietary iron on gene regulation of lactoferrin in mouse mammary gland.

This study evaluated the developmental gene expression of lactoferrin (LF) and the effect of supplementary iron on gene expression of LF in the mammary gland of mice using semi-quantitative reverse transcription-polymerase chain reaction (RT-PCR) analysis. In experiment 1, a total of 12 female mice were used to determine the effect of different lactating stages on mRNA expression of LF. The Institute of Cancer Research mice were divided into 4 groups; each group of 3 mice was tested on d 1, 9, 17, and 25 of lactation. In experiment 2, 6 groups of mice (total of 24 female mice at d 12 after mating) were fed purified diets (without iron or supplement iron) and were assigned to 2 treatments (control and treatment). The experimental feeding period lasted 35 d. During the feeding experiment, 6 mice (3 animals in each group) were chosen on d 1, 9, 17, and 25 of lactation to determine the effect of iron on LF mRNA expression of mice at different stages of lactation. The results of experiment 1 showed that LF mRNA had strong expression on d 1 of lactation, decreased gradually on d 9 and 17 of lactation, and then increased again markedly on d 25 of lactation. These results imply that the expression of LF in the mammary gland at different lactating stages is consistent with the changes in LF concentrations in milk. Iron significantly increased LF mRNA expression on d 1 and 25 of lactation. Iron did not statistically increase LF gene expression on d 9 and 17 of lactation. These findings raised the possibility that iron supplementation may play a role in regulation of LF levels in vivo.

Animals↗

PubMed1999

High sequence turnover in the regulatory regions of the developmental gene hunchback in insects.

Extensive sequence analysis of the developmental gene hunchback and its 5' and 3' regulatory regions in Drosophila melanogaster, Drosophila virilis, Musca domestica, and Tribolium castaneum, using a variety of computer algorithms, reveals regions of high sequence simplicity probably generated by slippage-like mechanisms of turnover. No regions are entirely refractory to the action of slippage, although the density and composition of simple sequence motifs varies from region to region. Interestingly, the 5' and 3' flanking regions share short repetitive motifs despite their separation by the gene itself, and the motifs are different in composition from those in the exons and introns. Furthermore, there are high levels of conservation of motifs in equivalent orthologous regions. Detailed sequence analysis of the P2 promoter and DNA footprinting assays reveal that the number, orientation, sequence, spacing, and protein-binding affinities of the BICOID-binding sites varies between species and that the 'P2' promoter, the nanos response element in the 3' untranslated region, and several conserved boxes of sequence in the gene (e.g., the two zinc-finger regions) are surrounded by cryptically-simple-sequence DNA. We argue that high sequence turnover and genetic redundancy permit both the general maintenance of promoter functions through the establishment of coevolutionary (compensatory) changes in cis- and trans-acting genetic elements and, at the same time, the possibility of subtle changes in the regulation of hunchback in the different species.

Amino Acid Sequence↗

PubMed2001

BldD is a direct regulator of key developmental genes in Streptomyces coelicolor A3(2).

BldD is a transcription factor required for aerial hyphae formation in the filamentous bacterium Streptomyces coelicolor. Three targets of BldD regulation were discovered by a number of means, including examination of bld gene interdependence, selective enrichment of chromosomal DNA fragments bound by BldD and searching the promoter regions of known developmental genes for matches to a previously characterized BldD binding site. The three BldD targets identified were the developmental sigma factor genes, whiG and bldN, and a previously uncharacterized gene, designated bdtA, encoding a putative transcription factor. In each target gene, the sequences bound by BldD were characterized by electrophoretic mobility shift and DNase I footprinting assays, and their alignment suggested AGTgA (n)m TCACc as a consensus BldD operator. The in vivo effect of mutation in bldD on the expression of these three target genes was assessed using S1 nuclease protection assays. In each case, target gene expression was upregulated during early colony development in the bldD background, suggesting that, in the wild type, BldD acts to repress premature expression of whiG, bldN and bdtA during vegetative growth.

Bacterial Proteins↗

PubMed2006

Recapitulation of embryological programmes in renal fibrosis--the importance of epithelial cell plasticity and developmental genes.

Chronic fibrosis represents the final common pathway in progressive renal disease. Myofibroblasts deposit the constituents of renal scar, thus crippling renal function. It has recently emerged that an important source of these pivotal effector cells is the injured renal epithelium. This review concentrates on the process of epithelial-mesenchymal transition (EMT) and its regulation. The role of the developmental gene, gremlin, which is reactivated in adult renal disease, is the subject of particular focus. This member of the cysteine knot protein superfamily is critical to the process of nephrogenesis but quiescent in normal adult kidney. There is increasing evidence that gremlin expression reactivates in diabetic nephropathy, and in the diseased fibrotic kidney per se. Known to antagonize members of the bone morphogenic protein (BMP) family, gremlin may also act downstream of TGF-beta in induction of EMT. An increased understanding of the extracellular modulation of EMT and, in particular, of the gremlin-BMP axis may result in strategies that can halt or reverse the devastating progression of chronic renal fibrosis.

Animals↗

PubMed2006

Identification of depot-specific human fat cell progenitors through distinct expression profiles and developmental gene patterns.

Anatomically separate fat depots differ in size, function, and contribution to pathological states, such as the metabolic syndrome. We isolated preadipocytes from different human fat depots to determine whether the basis for this variation is partly attributable to differences in inherent properties of fat cell progenitors. We found that genome-wide expression profiles of primary preadipocytes cultured in parallel from abdominal subcutaneous, mesenteric, and omental fat depots were distinct. Interestingly, visceral fat was not homogeneous. Preadipocytes from one of the two main visceral depots, mesenteric fat, had an expression profile closer to that of subcutaneous than omental preadipocytes, the other main visceral depot. Expression of genes that regulate early development, including homeotic genes, differed extensively among undifferentiated preadipocytes isolated from different fat depots. These profiles were confirmed by real-time PCR analysis of preadipocytes from additional lean and obese male and female subjects. We made preadipocyte strains from single abdominal subcutaneous and omental preadipocytes by expressing telomerase. Depot-specific developmental gene expression profiles persisted for 40 population doublings in these strains. Thus, human fat cell progenitors from different regions are effectively distinct, consistent with different fat depots being separate mini-organs.

Adipose Tissue↗

PubMed2005

Molecular evolution of the primate developmental genes MSX1 and PAX9.

In primates, the craniofacial skeleton and the dentition are marked by high levels of interspecific variation. Despite this, there are few comparative species studies conducted at the molecular level to investigate this functional diversity. We have determined nucleotide sequences of MSX1 and PAX9, two developmental genes, in a sample of 27 diverse primate species in order to identify coding or regulatory variation that may be associated with phenotypic diversity. Our analyses have identified four highly conserved noncoding sequences, including one that is conserved across primates and with dogs but not with mice. Although we find that substitution rates vary significantly across MSX1 exons, comparisons of nonsynonymous and synonymous substitution rates (dN/dS) suggest that, as a whole, MSX1 and PAX9 amino acid sequences have been under functional constraint throughout primate evolution. Compared to all other primates in our sample, our analysis of exon 1 in MSX1 finds an unusual pattern of amino acid substitution for Tarsius syrichta, a member of a lineage (tarsiers) that has many unique features among primates. For example, tarsiers are the only extant primates without deciduous incisors, and MSX1 is expressed exclusively in the incisor regions during the earliest stages of dental development. Our overall results provide insight into the utility of comparative species analyses of highly conserved developmental genes and their roles in the evolution of complex phenotypes.

Amino Acid Sequence↗

PubMed2005

The identification and functional characterisation of conserved regulatory elements in developmental genes.

Understanding the mechanisms that govern the expression of genomes is one of the major challenges of the post-genomic era. Phylogenetic footprinting, which identifies genomic regions under evolutionary constraints, has proven helpful in finding cis-regulatory elements of transcription; however, this method may not be applicable across all evolutionary distances and for all types of genes. Recent results from vertebrate comparisons indicate that strong conservation of cis-regulatory regions may occur more frequently in developmental regulator genes. This paper reviews methods of identifying conserved regulatory elements of developmental genes by comparative genomics, including new attempts to detect conserved features beyond simple sequence similarities. The results obtained are outlined and the authors comment on their functional and evolutionary implications. Finally, an evaluation of currently available methods of characterising the function of presumed conserved regulatory regions is presented, and problems such as promoter compatibility, assigning distant elements to their cognate genes and multifunctionality of elements, discussed.

Animals↗

PubMed1995

Developmental genes as a potential tool in population ecology of complex animal life cycles?

Many aquatic invertebrates possess complex life cycles, which include a switch from a vegetative to a sexual mode of reproduction. While sexual reproduction is usually linked to slow rates of propagation, vegetative reproduction leads to high rates of clonal propagation and a fast increase in population size. I have attempted to identify developmental genes which are differentially expressed between sexually and vegetatively reproducing individuals. quantitative assays of the expression of those diagnostic genes could be applied to field samples to gain information on the reproductive status of the sample. Here I outline a general strategy for identifying and testing the usefulness of homeobox genes as candidates for regulatory genes whose expression patterns are indicative of a sexual or vegetative developmental phase.

Animals↗

PubMed2006

Altered expression of pro-inflammatory and developmental genes in the fetal brain in a mouse model of maternal infection.

Human studies of unexplained cerebral palsy (CP) suggest an association with maternal infection. We used an established model of maternal infection, lipopolysaccharide (LPS) administration, to investigate the molecular changes in the fetal brain that may link maternal infection and CP. We compared gene expression in brains from mouse pups exposed to LPS in utero to those from saline-treated controls. Dams were injected with 50 microg LPS or saline on E18 with surgical delivery from 0.5 to 6h later. Differential gene expression was analyzed in the whole mouse brain using RT-PCR. When compared to control mice, pups exposed to LPS showed increased expression of pro-inflammatory genes monocyte chemoattractant protein-1 (MCP-1), interleukin-6 (IL-6), and interleukin-1beta (IL-1beta), as well as VEGF, a regulator of vascular development and permeability, the anti-apoptotic protein Y-box-binding protein-1 (YB-1), and the neuronal differentiation factor necdin. LPS-exposed mice also showed downregulation of semaphorin 5b and groucho, involved in axon guidance and neurogenesis, respectively, providing evidence that LPS may disrupt normal developmental pathways. These data suggest possible mechanisms for adverse neurological outcomes following maternal infection involving elevated cytokine levels and altered expression of developmental genes in the fetal brain.

Analysis of Variance↗

PubMed1986

Intercellular signaling is required for developmental gene expression in Myxococcus xanthus.

Certain developmental mutants of Myxococcus xanthus can be complemented (extracellularly) by wild-type cells. Insertions of Tn5 lac (a transposon which couples beta-galactosidase expression to exogenous promoters) into developmentally regulated genes were used to investigate extracellular complementation of the A group mutations. A- mutations reduced developmental beta-galactosidase expression from 18 of 21 Tn5 lac insertions tested and that expression was restored to A- Tn5 lac cells by adding wild-type cells. The earliest A-dependent Tn5 lac normally expresses beta-galactosidase at 1.5 hr of development indicating a developmental block at 1-2 hr in A- mutants. A substance which can rescue the expression of this early Tn5 lac is released by wild-type (A+) but not by A- cells. This substance appears in a cell-free wash of wild-type cells or in starvation buffer conditioned by wild-type cells 1-2 hr after development is initiated. The conditioned starvation buffer also restores normal morphological development to an A- mutant.

Bacterial Proteins↗

PubMed1995

Identification, characterization, and localization to chromosome 17q21-22 of the human TBX2 homolog, member of a conserved developmental gene family.

The T-box motif is present in a family of genes whose structural features and expression patterns support their involvement in developmental gene regulation. Previously, sequence comparisons among the T-box domains of ten vertebrate and invertebrate T-box (Tbx) genes established a phylogenetic tree with three major branches. The Tbx2-related branch includes mouse Mm-Tbx2 and Mm-Tbx3, Drosophila optomotor-blind (Dm-Omb), and Caenorhabditis elegans Ce-Tbx2 and Ce-Tbx2 and Ce-Tbx7 genes. From the localization of Mm-Tbx2 to Chromosome (Chr) 11, we focused our search for the human homolog, Hs-TBX2, within a region of synteny conservation on Chr 17q. We used Dm-Omb polymerase chain reaction (PCR) primers to amplify a 137-basepair(bp)_ product from human genomic, Chr 17 monochromosome hybrid, and fetal kidney cDNA templates. The human PCR product showed 89% DNA sequence identity and 100% peptide sequence identity to the corresponding T-box segment of Mm-Tbx2. The putative Hs-TBX2 locus was isolated within a YAC contig that included three anonymous markers, D17S792, and D17S948, located at Chr 17q21-22. Hybridization-and PCR-based screening of a 15-week fetal kidney cDNA library yielded several TBX2 clones. Sequence analysis of clone lambda omicron TBX2-1 confirmed homology to Mm-TBx2-90% DNA sequence identity over 283 nt, and 96% peptide sequence identity over 94 amino acids. Similar analysis of Hs-TBX2 cosmid 154F11 confirmed the cDNA coding sequence and also identified a 1.7-kb intron located at the same relative position as in Mm-Tbx2. Phylogenetic analyses of the T-box domain sequences found in several vertebrate and invertebrate species further suggested that the putative human TBX2 and mouse Tbx2 are true homologs. Northern blot analysis identified two major TBX2 expression fetal kidney and lung; and in adult kidney, lung, ovary, prostate, spleen, and testis. Reduced expression levels were seen in heart, white blood cells, small intestine, and thymus. These results suggest that Hs-TBX2 could play important roles in both developmental and postnatal gene regulation.

Amino Acid Sequence↗