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PubMed1986

Mechanisms of DNA sequence amplification and their evolutionary consequences.

DNA sequence amplification is a phenomenon that occurs predictably at defined stages during normal development in some organisms and has been shown to occur spontaneously, but sporadically, in a variety of cells, including mammalian cells, selected for overproduction of a gene product. Developmentally programmed gene amplification includes rDNA amplification during oögenesis in amphibia, chorion protein gene amplification in Drosophila and the chromosomal changes accompanying macronuclear formation in ciliates. Selected gene amplification is illustrated by mutant mammalian cells which have been selected in vitro or in vivo for the overproduction of a gene product. In these cells the unit of DNA that is amplified is much larger than the gene under selection, and appears to be formed by multiple recombination events, which bring together sequences not normally adjacent to each other. Often the product of amplification can be seen microscopically as aberrant chromosome forms. The vast majority of DNA amplification events occur in somatic nuclei, and thus would not have any direct effect on the evolution of a genome. However, the ability to amplify DNA in somatic cells does have consequences for the composition of the genomes of the organisms in which it can occur, and should DNA amplification occur, even sporadically, in germ-line cells the potential effect on evolution would be great.

Amphibians↗
PubMed2001

On the evolution of early development in the Nematoda.

The phylum Nematoda serves as an excellent model system for exploring how development evolves, using a comparative approach to developmental genetics. More than 100 laboratories are studying developmental mechanisms in the nematode Caenorhabditis elegans, and many of the methods that have been developed for C. elegans can be applied to other nematodes. This review summarizes what is known so far about steps in early development that have evolved in the nematodes, and proposes potential experiments that could make use of these data to further our understanding of how development evolves. The promise of such a comparative approach to developmental genetics is to fill a wide gap in our understanding of evolution--a gap spanning from mutations in developmental genes through to their phenotypic results, on which natural selection may act.

Animals↗
PubMed1997

Differential HSC70 expression during asexual development of Neurospora crassa.

The constitutive and the heat-shock-induced expression of members of heat-shock protein families changed during vegetative development and conidiation of Neurospora crassa as determined by two-dimensional gel electrophoresis. Western blot and ELISA analyses revealed the highest amounts of the constitutive heat-shock protein 70 (HSC70) in conidiating aerial hyphae and dormant conidia. During conidial germination the amount of HSC70 decreased and subsequently increased during vegetative growth. Stationary mycelia and young aerial hyphae exhibited the lowest HSC70 level. The stationary-phase-dependent decrease in HSC70 was accompanied by a concomitant increase in its nuclear localization, whereas no significant changes in the amount of nuclear HSC70 were found during aerial hyphae development. The cAMP content during aerial hyphae development was inversely correlated with that of HSC70. To examine possible causal relations between HSC70 expression and cAMP content, the adenylate-cyclase-deficient mutant crisp (cr-1) was analysed, which exhibits low concentrations of endogenous cAMP. This mutant, however, showed a lower constitutive HSC70 level, compared to the bdA strain. Treatment of the bd strain and cr-1 mutant with 20 microM 8-bromo-cAMP did not result in significant changes of the constitutive HSC70 level, but in the level of heat-induced HSC/HSP70. In a developmental mutant (acon-2) which is defective in a differentiation step toward conidiation, the expression of HSC70 in aerial hyphae was delayed until the first proconidial chains were observed. It is concluded that the differential expression of HSC/HSP70 does not depend on different nuclear levels of HSC70 or on changes in cAMP concentrations, but rather on developmental genes controlling conidiation.

8-Bromo Cyclic Adenosine Monophosphate↗
PubMed1997

HBP1: a HMG box transcriptional repressor that is targeted by the retinoblastoma family.

A prominent feature of cell differentiation is the initiation and maintenance of an irreversible cell cycle arrest with the complex involvement of the retinoblastoma (RB) family (RB, p130, p107). We have isolated the HBP1 transcriptional repressor as a potential target of the RB family in differentiated cells. By homology, HBP1 is a sequence-specific HMG transcription factor, of which LEF-1 is the best-characterized family member. Several features of HBP1 suggest an intriguing role as a transcriptional and cell cycle regulator in differentiated cells. First, inspection of the HBP1 protein sequence revealed two consensus RB interaction motifs (LXCXE and IXCXE). Second, HBP1 interaction was selective for RB and p130, but not p107. HBP1, RB, and p130 levels are all up-regulated with differentiation; in contrast, p107 levels decline. Third, HBP1 can function as a transcriptional repressor of the promoter for N-MYC, which is a critical cell cycle and developmental gene. Fourth, because the activation of the N-MYC promoter in cycling cells required the E2F transcription factor, we show that E2F-1 and HBP1 represent opposite transcriptional signals that can be integrated within the N-MYC promoter. Fifth, the expression of HBP1 lead to efficient cell cycle arrest. The arrest phenotype was manifested in the presence of optimal proliferation signals, suggesting that HBP1 exerted a dominant regulatory role. Taken together, the results suggest that HBP1 may represent a unique transcriptional repressor with a role in initiation and establishment of cell cycle arrest during differentiation.

Animals↗
PubMed1991

The paired box encodes a second DNA-binding domain in the paired homeo domain protein.

The homeo box, which encodes the DNA-binding homeo domain, is a DNA sequence motif present in several Drosophila developmental genes; it has been used to identify many homologous genes involved in mammalian development. The paired box is another conserved sequence motif, first identified in the paired (prd) and gooseberry (gsb) Drosophila homeo domain genes. It encodes a 128-amino-acid domain, the paired domain, which has since been found in other fly and mouse gene products, in association with the homeo domain or in its absence. We show that the paired box of the prd gene encodes a DNA-binding activity, independent of the DNA-binding activity of the Paired (Prd) homeo domain and with a different sequence specificity. The amino-terminal region of the paired domain, including one of the three predicted alpha-helices, is necessary and sufficient for binding. We investigate the binding of the Prd protein to two sites in the even-skipped promoter, which are composed of overlapping sequences bound by the homeo domain and by the paired domain. We also show that a mutation in the paired box of Prd, corresponding to the mutation in the paired box of the mouse Pax-1 gene thought to cause the undulated skeletal phenotype, destroys the ability of the Prd protein to bind to the paired domain-specific site. This supports the view that the undulated phenotype results from the inactivation of the DNA-binding activity of the paired domain of Pax-1.

Animals↗
PubMed2002

G9a histone methyltransferase plays a dominant role in euchromatic histone H3 lysine 9 methylation and is essential for early embryogenesis.

Covalent modification of histone tails is crucial for transcriptional regulation, mitotic chromosomal condensation, and heterochromatin formation. Histone H3 lysine 9 (H3-K9) methylation catalyzed by the Suv39h family proteins is essential for establishing the architecture of pericentric heterochromatin. We recently identified a mammalian histone methyltransferase (HMTase), G9a, which has strong HMTase activity towards H3-K9 in vitro. To investigate the in vivo functions of G9a, we generated G9a-deficient mice and embryonic stem (ES) cells. We found that H3-K9 methylation was drastically decreased in G9a-deficient embryos, which displayed severe growth retardation and early lethality. G9a-deficient ES cells also exhibited reduced H3-K9 methylation compared to wild-type cells, indicating that G9a is a dominant H3-K9 HMTase in vivo. Importantly, the loss of G9a abolished methylated H3-K9 mostly in euchromatic regions. Finally, G9a exerted a transcriptionally suppressive function that depended on its HMTase activity. Our results indicate that euchromatic H3-K9 methylation regulated by G9a is essential for early embryogenesis and is involved in the transcriptional repression of developmental genes.

Acetylation↗
PubMed2026

Fetal signatures in the 3D genome of iPSC-derived neurons and their implications for disease modeling.

Induced pluripotent stem cells (iPSCs) have revolutionized neuroscience, providing an approach to generate patient-specific neurons for modeling of neurological diseases. However, it remains unclear how closely iPSC-derived neurons replicate the chromatin architecture of authentic brain neurons. Here, we uniformly processed newly generated Hi-C data from iPSC-derived neurons and neurons isolated from the human postmortem brain, together with previously published data sets comprising 228 human and 89 mouse Hi-C and snm3C-seq samples from different cell subtypes. These data were merged into 96 high-coverage contact maps used to examine chromatin features ranging from chromatin compartments and topologically associating domains (TADs) to chromatin loops, Polycomb-mediated contacts, and frequently interacting regions (FIREs). We find that iPSC-derived neurons largely retain the chromatin state of undifferentiated cells and resemble fetal rather than mature neurons. iPSC-derived neurons exhibit unusually strong compartmentalization, an enrichment of developmental genes at TAD borders, and a marked reduction of long-range repressive Polycomb-mediated contacts that typically silence early fetal programs. Although immature, iPSC-derived neurons offer advantages for modeling interactions between disease-associated SNPs and target genes, as many psychiatric disorders have neurodevelopmental origins. Integrating iPSC-derived and postmortem neuronal data sets therefore provides complementary insights into the chromatin landscape underlying disease-associated interactions. Our study offers a valuable Hi-C resource for the community and provides a detailed comparison of chromatin architecture throughout neuronal maturation, underscoring its importance for validating neuronal models and providing a robust framework for future studies.

Journal Article↗
PubMed1999

Linker histones play a role in male meiosis and the development of pollen grains in tobacco.

To examine the function of linker histone variants, we produced transgenic tobacco plants in which major somatic histone variants H1A and H1B were present at approximately 25% of their usual amounts in tobacco chromatin. The decrease in these major variants was accompanied by a compensatory increase in the four minor variants, namely, H1C to H1F. These minor variants are smaller and less highly charged than the major variants. This change offered a unique opportunity to examine the consequences to a plant of major remodeling of its chromatin set of linker histones. Plants with markedly altered proportions of H1 variants retained normal nucleosome spacing, but their chromosomes were less tightly packed than those of control plants. The transgenic plants grew normally but showed characteristic aberrations in flower development and were almost completely male sterile. These features correlated with changes in the temporal but not the spatial pattern of expression of developmental genes that could be linked to the abnormal flower phenotypes. Preceding these changes in flower morphology were strong aberrations in male gametogenesis. The earliest symptoms may have resulted from disturbances in correct pairing or segregation of homologous chromosomes during meiosis. No aberrations were observed during mitosis. We conclude that in plants, the physiological stoichiometry and distribution of linker histone variants are crucial for directing male meiosis and the subsequent development of functional pollen grains.

Chromatin↗
PubMed2005

Coupling of multicellular morphogenesis and cellular differentiation by an unusual hybrid histidine protein kinase in Myxococcus xanthus.

We describe an unusual hybrid histidine protein kinase, which is important for spatially coupling cell aggregation and sporulation during fruiting body formation in Myxococcus xanthus. A rodK mutant makes abnormal fruiting bodies and spores develop outside the fruiting bodies. RodK is a soluble, cytoplasmic protein, which contains an N-terminal sensor domain, a histidine protein kinase domain and three receiver domains. In vitro phosphorylation assays showed that RodK possesses kinase activity. Kinase activity is essential for RodK function in vivo. RodK is present in vegetative cells and remains present until the late aggregation stage, after which the level decreases in a manner that depends on the intercellular A-signal. Genetic evidence suggests that RodK may regulate multiple temporally separated events during fruiting body formation including stimulation of early developmental gene expression, inhibition of A-signal production and inhibition of the intercellular C-signal transduction pathway. We speculate that RodK undergoes a change in activity during development, which is reflected in changes in phosphotransfer to the receiver domains.

Amino Acid Sequence↗
PubMed2006

Global transcriptional upregulation in the absence of increased translation in Chlamydia during IFNgamma-mediated host cell tryptophan starvation.

The developmentally regulated intracellular pathogen Chlamydia pneumoniae is a natural tryptophan auxotroph. These organisms survive tryptophan starvation induced by host cell activation with IFNgamma by blocking maturation to the infectious form. In most bacteria, the stringent response is induced during amino acid starvation to promote survival. However, the response of obligate intracellular pathogens, which are predicted to lack stringent responses to amino acid starvation, is poorly characterized. Chlamydial transcription and translation were analysed during IFNgamma-mediated tryptophan starvation using genomic normalization methods, and the data revealed the novel findings that: (i) global chlamydial transcription was upregulated; and (ii) protein synthesis was dramatically reduced. These results indicate a dysregulation of developmental gene expression and an uncoupling of transcription from translation. These observations represent an alternative survival strategy for host-adapted obligate intracellular bacterial pathogens that have lost the genes for stringent control during reductive evolution.

Cell Line↗
PubMed2005

Discrepancies in upper and lower limb patterning in split hand foot malformation.

Discrepancies in upper and lower limb patterning in split hand foot malformation. Split hand foot malformation (SHFM) is genetically heterogeneous with five loci mapped to date. Highly variable in presentation, it can occur as an isolated finding or with other anomalies. The genetic heterogeneity and clinical variability make genetic counselling of SHFM families challenging. By establishing genotype/phenotype correlations, one can provide insight into responsible developmental genes and help to direct mapping efforts and target genetic testing, ultimately providing more accurate information for family members. Preaxial involvement of the upper extremities was a significant discriminating limb-specific variable in our analysis of genetically mapped SHFM cases. This finding, which was originally identified through descriptive epidemiology, was subsequently confirmed by discriminant function analysis (p < 0.0001) to be a significant locus discriminator. Preaxial involvement of the upper extremities was most commonly seen at the SHFM3 locus mapped to chromosome 10q24 (OMIM 600095) and consisted of proximally placed thumbs and/or triphalangeal thumbs (TPT), preaxial polydactyly and/or absence of the first ray. These patients' feet, however, tended to show a classical central longitudinal deficiency without a significant preaxial component. This article discusses this discrepant clefting pattern between the upper and lower extremities and proposes potential mechanisms.

Abnormalities, Multiple↗
PubMed1987

Density-dependent induction of discoidin-I synthesis in exponentially growing cells of Dictyostelium discoideum.

The synthesis of the lectin, discoidin I, by vegetative cells of Dictyostelium discoideum (strain NC4) was monitored using immunoblot analysis and indirect immunofluorescence. Suspension cultures were used, so that the D. discoideum cell density and the concentration of bacteria could be controlled. Discoidin-I production was found to be a function of the relative densities of D. discoideum cells and food bacteria. Synthesis was initiated in exponentially growing D. discoideum cells approximately three generations before depletion of the food supply. In the growth medium of cells producing discoidin I, a soluble activity was detected that caused low-density cells to begin discoidin-I synthesis. This activity was not dialyzable and was destroyed by heat. A similar activity was produced by AX3 cells during axenic growth. Density-dependent induction of other 'early developmental' proteins was also detected in wild-type cells. These findings suggest that the expression of several 'early developmental' genes is regulated by a mechanism that measures cell density relative to food supply, not by starvation per se.

Cell Differentiation↗
PubMed2004

piggyBac-mediated somatic transformation of the two-spotted cricket, Gryllus bimaculatus.

Transgenic insects have been artificially produced to study functions of interesting developmental genes, using insect transposons such as piggyBac. In the case of the cricket, however, transgenic animals have not yet been successfully artificially produced. In the present study, we examined whether the piggyBac transposon functions as a tool for gene delivery in embryos of Gryllus bimaculatus. We used either a piggyBac helper plasmid or a helper RNA synthesized in vitro as a transposase source. An excision assay revealed that the helper RNA was more effective in early Gryllus eggs to transpose a marker gene of eGFP than the helper plasmid containing the piggyBac transposase gene driven by the G. bimaculatus actin3/4 promoter. Further, only when the helper RNA was used, somatic transformation of the embryo with the eGFP gene was observed. These results suggest that the piggyBac system with the helper RNA may be effective for making transgenic crickets.

Animals↗
PubMed2006

The evolution of development in Streptomyces analysed by genome comparisons.

There is considerable information about the genetic control of the processes by which mycelial Streptomyces bacteria form spore-bearing aerial hyphae. The recent acquisition of genome sequences for 16 species of actinobacteria, including two streptomycetes, makes it possible to try to reconstruct the evolution of Streptomyces differentiation by a comparative genomic approach, and to place the results in the context of current views on the evolution of bacteria. Most of the developmental genes evaluated are found only in actinobacteria that form sporulating aerial hyphae, with several being peculiar to streptomycetes. Only four (whiA, whiB, whiD, crgA) are generally present in nondifferentiating actinobacteria, and only two (whiA, whiG) are found in other bacteria, where they are widespread. Thus, the evolution of Streptomyces development has probably involved the stepwise acquisition of laterally transferred DNA, each successive acquisition giving rise either to regulatory changes that affect the conditions under which development is initiated, or to changes in cellular structure or morphology.

Bacterial Proteins↗
PubMed1994

Increasing melanoma incidence: putatively explainable by retrotransposons. Experimental contributions of the xiphophorine Gordon-Kosswig melanoma system.

The worldwide accelerating increase of neoplasia in humans is difficult to explain. We use the Xiphophorus tumor model to approach this problem by melanoma provocation with X-rays. Melanoma develops following inappropriate expression of x-erb B-conducted developmental genes and their controllers. These oncodeterminants are inherited according to Mendelian rules. We detected a new type of oncodeterminants that, following a single treatment of embryos with X-rays, generates a self-generating non-Mendelian melanoma transmission and accelerating increase of its incidence in succeeding generations (e.g., 0-->18-->33-->52%). To localize these oncodeterminants, we crossed nonirradiated fish having half of their chromosomes irradiated with nonirradiated fish having none of, half of, or all of their chromosomes irradiated. Because tumor rate and expression in the following generations correspond to the rates of treated chromosomes, we conclude that the new oncodeterminants are distributed over the chromosomes of the fish, where they may increase in the changing generations. By means of xiphophorine-specific retroviral DNA, we isolated two retrotransposons that behave hereditarily like the new transgenerational oncodeterminants. Sequence analysis revealed three ORFs flanked by LTRs containing motives of regulatory sequences typical for known retroviral and retrotransposal LTRs. Pol- and env-resembling sequences are lacking. Southern and in situ hybridization showed their multiple and repetitive nature distributed throughout the chromosomes and indications for their capability to increase in number without further treatment. Their transcripts are expressed in concert with those of most of the other known xiphophorine tumor determinants. Their expression is extremely high in cell cultures from tumorous embryos derived from ancestors treated as embryos with X-rays.

Animals↗
PubMed2006

The homeobox HOXB13 is expressed in human minor salivary gland.

BACKGROUND: Homeobox are a family of developmental genes involved in morphogenesis and cellular differentiation. Participation of homeobox within normal and malignant tissue has been recently discussed in the literature. OBJECTIVE: To analyze the presence of HOXB13 transcript expression in human minor salivary gland. MATERIAL AND METHODS: Ten-micrometer sections from frozen samples were evaluated employing non-radioactive in situ hybridization technique and HOXB13 mRNA probes. RESULTS: HOXB13 was found to be expressed in ducts and mucous acini but not in serous acini. CONCLUSIONS: RESULTS suggest that HOXB13 transcripts are differently expressed in normal mucous and serous acini, and it may possibly reflect a different role in salivary gland carcinogenesis.

Carcinoma, Squamous Cell↗
PubMed2003

The amygdala and its place in the cerebral hemisphere.

Developmental, gene expression, connectional, and neuron morphology evidence converges to suggest that cell groups of the amygdalar region participate in at least four distinct, though interrelated, functional systems associated with differentiated corticostriatopallidal projections. The amygdala is neither a structural nor a functional unit; instead, it is a collection of adjacent cell groups in the medial temporal lobe and adjacent regions of the caudal piriform lobe that was defined on gross anatomic terms.

Amygdala↗
PubMed1990

Cell alignment required in differentiation of Myxococcus xanthus.

During fruiting body morphogenesis of Myxococcus xanthus, cell movement is required for transmission of C-factor, a short range intercellular signaling protein necessary for sporulation and developmental gene expression. Nonmotile cells fail to sporulate and to express C-factor-dependent genes, but both defects were rescued by a simple manipulation of cell position that oriented the cells in aligned, parallel groups. A similar pattern of aligned cells normally results from coordinated recruitment of wildtype cells into multicellular aggregates, which later form mature fruiting bodies. It is proposed that directed cell movement establishes critical contacts between adjacent cells, which are required for efficient intercellular C-factor transmission.

Bacterial Proteins↗