bluuebunny/crossref_metadata_2025 huggingface dataset:
The making of a fly leg: A model for epithelial morphogenesis
Authors: von Kalm Laurence , Fristrom Dianne , Fristrom James
Published: February 2005

Epithelial development dictates the shape of an organism. The metamorphic development of a Drosophila leg precursor into an adult leg is a well‐defined example of epithelial morphogenesis that can be analyzed from the perspectives of genetics and molecular and cell biology. The steroid hormone 20‐hydroxyecdysone induces and regulates the entire process. Mutants affecting Drosophila leg morphogenesis characteristically have short thick legs (the malformed phenotype) resulting from a failure to execute normal cell shape changes at a specific stage of development. Mutations that cause the malformed phenotype have already led to the identification and cloning of genes encoding transcription factors, a transmembrane serine protease presumably required for modification of the apical extracellular matrix, and components of the contractile cytoskeleton and adherens junctions. All of these products are required for the execution of normal changes in leg cell shape.
Structure and function of apurinic/apyrimidinic endonucleases
Authors: Barzilay Gil , Hickson Ian D.
Published: February 2005

The DNA of all species is constantly under threat from both endogenous and exogenous factors, which damage its chemical structure. Probably the most common lesion that arises in cellular DNA is the loss of a base to generate an abasic site, which is usually referred to as an apurinic or apyrimidinic (AP) site. Since these lesions are potentially both cytotoxic and mutagenic, cells of all organisms express dedicated repair enzymes, termed AP endonucleases, to counteract their damaging effects. Indeed, many organisms consider it necessary to express two or more of these lesion‐specific endonucleases, underscoring the requirement that exists to remove AP sites for the maintenance of genome integrity and cell viability. Most AP endonucleases are very versatile enzymes, capable of performing numerous additional repair roles. In this article, we review the AP endonuclease class of repair enzymes, with emphasis on the evolutionary conservation of structural features, not only between prokaryotic and eukaryotic homologues, but also between these enzymes and the RNase H domain of one class of reverse transcriptase.
Instability of inhibited replication forks in E. coli
Authors: Kuzminov Andrei
Published: February 2005

Inhibiting the progress of replication forks in E. coli makes them susceptible to breakage. Broken replication forks are evidently reassembled by the RecBCD recombinational repair pathway. These findings explain a particular pattern of DNA degradation during inhibition of chromosomal replication, the role of recombination in the viability of mutants with displaced replication origin, and hyper‐recombination observed in the Terminus of the E. coli chromosome in rnh mutants. Breakage and repair of inhibited replication forks could be the reason for the recombination‐dependence of inducible stable DNA replication. A mechanism by which RecABCD‐dependent recombination between very short inverted repeats may help E. coli to invert an operon, transcribed in the direction opposite to that of DNA replication, is discussed.
Recombination, mutation and the origin of species
Authors: Cox Edward C.
Published: February 2005

A major barrier to recombination between bacterial species lies in the mismatch repair system, a complex of proteins that has evolved to proof‐read freshly replicated DNA. It now appears that a second system, involving an inducible DNA recombination, repair and mutagenesis pathway, also regulates interspecies recombination, but in a positive way, being required for recombination between Escherichia coli and Salmonella typhimurium(1). Thus the rate at which newly emerging species of bacteria diverge can be seen as a balance between a permissive state associated with inducible repair and recombination, and the proof‐reading of intermediates in the recombination pathway by the mismatch correction system.
How many signals does it take?
Authors: Venkatesh T. V. , Bodmer Rolf
Published: February 2005

Although the genetics of dorsal‐ventral polarity which leads to mesoderm formation in Drosophila are understood in considerable detail, subsequent molecular mechanisms involved in patterning the mesoderm primordium into individual mesodermal subtypes are poorly understood. Two papers published recently (1,2) suggest strongly that an inductive signal from dorsal ectoderm is involved in subdividing the underlying mesoderm, and present evidence that one of the signalling factors is Decapentaplegic (Dpp), a member of the bone morphogenetic protein subgroup of the Transforming Growth Factor‐β (TGF‐β) super family of proteins.
Pattern and process of wall formation in developing endosperm
Authors: Olsen O.‐A. , Brown R. C. , Lemmon B. E.
Published: February 2005

Endosperm is emerging as a system for investigating the genetic control of wall placement and deposition in plant development. Development of endosperm progresses in distinct stages from a wall‐less syncytial stage to a cellular stage that is entirely typical of plant meristems where the division plane is predicted by a preprophase band of microtubules (PPB) and cytokinesis is completed by formation of a cell plate in association with a phragmoplast. Four developmentally different types of walls, each associated with a different microtubule system, are sequentially produced: (1) free growing walls deposited in the absence of mitosis and phragmoplasts; (2) walls guided by cytoplasmic phragmoplasts formed adventitiously in the absence of mitosis; (3) walls formed by interzonal phragmoplasts in a cell cycle that lacks PPBs; and (4) wall deposition driven by interzonal phragmoplasts in a cycle that includes PPBs. We are using methods of differential screening to isolate cDNA clones corresponding in temporal and spatial pattern to the types of wall development, and are studying mutants for clues to the genetic controls of wall development.
The specificity of homeotic gene function
Authors: Mann Richard S.
Published: February 2005

How transcription factors achieve their in vivo specificities is a fundamental question in biology. For the Homeotic Complex (HOM/Hox) family of homeoproteins, specificity in vivo is likely to be in part determined by subtle differences in the DNA binding properties inherent in these proteins. Some of these differences in DNA binding are due to sequence differences in the N‐terminal arms of HOM/Hox homeodomains. Evidence also exists to suggest that cofactors can modify HOM/Hox function by cooperative DNA binding interactions. The Drosophila homeoprotein extradenticle (exd) is likely to be one such cofactor. In HOM/Hox proteins, both the conserved ‘YPWM’ peptide motif and the homeodomain are important for interacting with exd. Although exd provides part of the answer as to how specificity is achieved, there may be additional cofactors and mechanisms that have yet to be identified.
Chromosomes take an active role in spindle assembly
Authors: Waters Jennifer C. , Salmon Edward D.
Published: February 2005

The assembly of a bipolar spindle is essential for the accurate segregation of replicated chromosomes during cell division. Do chromosomes rely solely on other cellular components to regulate the assembly of the bipolar spindle or are they masters of their own fate? In the Zhang and Nicklas(1) study reviewed here, micromanipulation techniques and video microscopy were used to demonstrate the different roles that chromosome arms, kinetochores and centrosomes play in bipolar spindle assembly.
Histone H4, the cell cycle and A question of integrity
Authors: Turner Bryan M.
Published: February 2005

The N‐terminal domain of histone H4 has been implicated in various nuclear functions, including gene silencing and activation and replication‐linked chromatin assembly. Many of these have been identified by using H4 mutants in the yeast S. cerevisiae. In a recent paper, Megee et al.(1) use this approach to show that mutants in which all four N‐terminal H4 lysines are substituted with glutamines accumulate increased levels of DNA damage. A single lysine, but not an arginine, anywhere in the N‐terminal domain suppresses this phenotype. It is suggested that histone H4 plays a role in maintaining genome integrity through the cell cycle, possibly by a mechanism involving lysine acetylation.
Inflammation, reproduction, cancer and all that…. The regulation and role of the inducible prostaglandin synthase
Authors: Herschman Harvey R. , Xie Weilin , Reddy Srinivasa
Published: February 2005

Discovery of a second, inducible prostaglandin synthase provides explanations for many previously puzzling observations, but also raises new questions about prostanoid synthesis. A cis‐acting sequence closely related to the cyclic AMP response element has been shown to play a role in both basal and induced prostaglandin synthase 2 gene expression. Aspirin and other currently available non‐steroidal anti‐inflammatory drugs that inhibit prostaglandin synthase activity do not effectively discriminate between the inducible prostaglandin synthase 2 and constitutive prostaglandin synthase 1 enzymes. Identification of a second prostaglandin synthase, induced by inflammatory stimuli, initiated a search for isoform‐specific inhibitors. Use of prostaglandin synthase 2 specific inhibitors and antisense oligonucleotides has led to the suggestion that specific ligands activate alternative pathways of prostanoid production, using one of the prostaglandin synthase isoforms preferentially. The coupling mechanisms by which these pathways are activated in response to alternative stimuli should provide additional routes of intervention in prostanoid production.
Happenstance, circumstance or enemy action: Cyclin D1 in breast, eye and brain
Authors: Schmidt Emmett V.
Published: February 2005

Two recent reports of mice homozygously deleted for cyclin D1 provide unequivocal evidence that the critical G1 cyclin, cyclin D1, is by itself rate‐limiting for growth in some mammalian tissues(1,2). Cyclin D1 knockout mice are small and exhibit behavioral abnormalities. Specific hypoplasias of retinal and mammary tissues suggest an unusual dependence on cyclin D1 function for tissue growth in those organs. The odd coincidences that cyclin D1 functions as the retinoblastoma gene kinase, together with associations between increased cyclin D1 expression and breast cancer, suggest, but do not prove, a special function of cyclin D1 in those tissues.
Temperature variation and sex determination in reptiles
Authors: Pieau Claude
Published: February 2005

In many species of reptiles, sex is determined at fertilization by zygotic sex chromosome composition. In other species, including all crocodilians, most turtles and some lizards, sex is determined by temperature during the earlier stages of gonadal differentiation. The effects of exogenous estrogens, antiestrogens and aromatase inhibitors at different temperatures have unambiguously demonstrated the involvement of estrogens in sexual differentiation of the gonads. Aromatase is the enzyme that converts androgens to estrogens. Gonadal aromatase activity is well correlated with gonadal structure. It increases exponentially in differentiating ovaries, whereas it remains low in differentiating testes. Moreover, there is a high correlation between the thermosensitive periods for both ovary differentiation and increase in aromatase activity. We suggest that a thermosensitive factor intervenes, directly or indirectly, in the transcriptional regulation of the aromatase gene in reptiles with temperature‐dependent sex determination.
Systemin – a polypeptide defense signal in plants
Authors: Schaller Andreas , Ryan Clarence A.
Published: February 2005

Insect and pathogen attacks activate plant defense genes within minutes in nearby cells, and within hours in leaves far distant from the sites of the predator attacks. A search for signal molecules involved in both the localized and distal signalling has resulted in the identification of an 18‐amino‐acid polypeptide, called systemin, that activates defense genes in leaves of tomato plants when supplied at levels as low as fmols/plant. Several lines of evidence support a role for systemin as a wound hormone. As with animal polypeptide hormones, systemin is derived from a larger precursor protein, called prosystemin, by limited proteolysis. Systemin has been shown by autoradiography to be phloemmobile and, by antisense technology, to be an essential component of the wound‐inducible, systemic signal transduction system leading to the transcriptional activation of the defensive genes. A search for the receptor of systemin has led to the identification in plant plasma membranes of a systeminbinding protein. However, this protein has properties not of a receptor, but of a furin‐like proteinase that cleaves systemin into smaller polypeptides. Systemin and its precursor prosystemin provide prototypes for the emerging possibilities that polypeptide hormones may have broad roles in signalling environmental stress responses, and in regulating plant growth and development as well.
Transcriptional regulation of the dihydrofolate reductase gene
Authors: Slansky Jill E. , Farnham Peggy J.
Published: February 2005

As cells approach S phase, many changes occur to create an environment conducive for DNA synthesis and commitment to cell division. The transcription rate of many genes encoding enzymes involved in DNA synthesis, including the dihydrofolate reductase (dhfr) gene, increases at the G1/S boundary of the cell cycle. Although a number of transcription factors interact to finely tune the levels of dhfr RNA produced, two families of transcription factors, Sp1 and E2F, play central roles in modulating dhfr levels. A region containing several Sp1‐binding sites is required for both regulated and basal transcription levels. In contrast, the E2F‐binding sites near the transcription start site are required only for regulated transcription. A model is presented for the regulation of the dhfr gene which may also pertain to other cell cycle‐associated genes.
The mechanism of bacterial asymmetric cell division
Authors: Way Jeffrey C.
Published: February 2005

Asymmetric cell division generates two cells that contain different regulatory proteins and express different fates. In an example of asymmetric cell division from B. subtilis, a site on the membrane of the dividing cell is chosen to establish the initial asymmetry. Recent results(1,2) show that a key regulatory protein, SpollE, is localized to one side of a sporulating B. subtilis cell, and subsequently functions in an asymmetric manner. SpollE is a phosphatase at the beginning of a regulatory cascade that leads to activation of a cell fate‐determining transcription factor in only one daughter cell.
The nature of quantittative genetic variation revisited: Lessons from Drosophila bristles
Authors: Mackay Trudy F. C.
Published: February 2005

Most characters that distinguish one individual from another, like height or weight, vary continuously in populations. Continuous variation of these ‘quantitative’ traits is due to the simultaneous segregation of multiple quantitative trait loci (QTLs) as well as environmental influences. A major challenge in human medicine, animal and plant breeding and evolutionary genetics is to identify QTLs and determine their genetic properties. Studies of the classic quantitative traits, abdominal and sternopleural bristle numbers of Drosophila, have shown that: (1) many loci have small effects on bristle number, but a few have large effects and cause most of the genetic variation; (2) ‘candidate’ loci involved in bristle development often have large quantitative effects on bristle number; and (3) alleles at QTLs affecting bristle number have variable degrees of dominance, interact with each other, and affect other quantitative traits, including fitness. Lessons learned from this model system will be applicable to studies of the genetic basis of quantitative variation in other species.
Chromatin diminution in nematodes
Authors: Müller Fritz , Bernard Vincent , Tobler Heinz
Published: February 2005

The process of chromatin diminution inParascarisandAscarisis a developmentally controlled genome rearrangement, which results in quantitative and qualitative differences in DNA content between germ line and somatic cells. Chromatin diminution involves chromosomal breakage, new telomere formation and DNA degradation. The programmed elimination of chromatin in presomatic cells might serve as an alternative way of gene regulation. We put forward a new hypothesis of how an ancient partial genome duplication and chromatin diminution may have served to maintain the genetic balance in somatic cells and simultaneously endowed the germ line cells with a selective advantage.
Sticky fingers: Hox genes and cell adhesion in vertebrate limb development
Authors: Newman Stuart A.
Published: February 2005

During vertebrate limb development, various genes of the Hox family, the products of which influence skeletal element identity, are expressed in specific spatiotemporal patterns in the limb bud mesenchyme. At the same time, the cells also exhibit ‘self‐organizing’ behavior – interacting with each other via extracellular matrix and cell‐cell adhesive molecules to form the arrays of mesenchymal condensations that lead to the cartilaginous skeletal primordia. A recent study by Yokouchi et al.(1) establishes a connection between these phenomena. They misexpressed the product of the Hoxa‐13 gene in chick limb buds and demonstrated both skeletal pattern perturbations and changes in cell‐cell adhesivity in mesenchyme aberrantly expressing this protein.
Kinesin proteins: A phylum of motors for microtubule‐based motility
Authors: Moore Jonathan D. , Endow Sharyn A.
Published: February 2005

The cellular processes of transport, division and, possibly, early development all involve microtubule‐based motors. Recent work shows that, unexpectedly, many of these cellular functions are carried out by different types of kinesin and kinesin‐related motor proteins. The kinesin proteins are a large and rapidly growing family of microtubule‐motor proteins that share a 340‐amino‐acid motor domain. Phylogenetic analysis of the conserved motor domains groups the kinesin proteins into a number of subfamilies, the members of which exhibit a common molecular organization and related functions. The kinesin proteins that belong to different subfamilies differ in their rates and polarity of movement along microtubules, and probably in the particles/organelles that they transport. The kinesins arose early in eukaryotic evolution and gene duplication has allowed functional specialization to occur, resulting in a surprisingly large number of different classes of these proteins adapted for intracellular transport of vesicles and organelles, and for assembly and force generation in the meiotic and mitotic spindles.
Deregulation of protein synthesis as a mechanism of neoplastic transformation
Authors: Rosenwald Igor B.
Published: February 2005

Early research on the cell cycle revealed correlations between protein accumulation and cell proliferation. In this review, I describe the data showing that abnormality of cell growth and tumor development are dependent upon oncogene‐induced increases in the levels and activity of factors that determine the rate of protein synthesis. It is proposed that the establishment of a vicious circle, namely oncoproteins → increase in translation → oncoproteins, is a major biological mechanism that fuels neoplastic growth. The constitutively high rates of protein synthesis and accumulation of proteins, including those necessary for DNA replication and mitosis, would drive cells to excessive proliferation.
The organizer formation: Two molecules are better than one
Authors: Lombardo Aurora
Published: February 2005

A recent paper by Watabe et al.(1) describes the identification, in the promoter region of the organizer‐specific gene goosecoid, of two distinct growth factor responsive elements that are required for the regulation of this gene both in vitro and in vivo. This is an important finding since it provides molecular evidence in support of the recently proposed model in which the production of dorsal type mesoderm is thought to require a synergistic interaction between a general mesoderm inducing factor and a dorsalizing competence modifier(2,6–8). Furthermore, the authors provide an elegant example of how a response element can become a useful tool to map the presence of a biologically available ligand within the embryo.
Brain POU‐er
Authors: Sharp Z. Dave , Morgan William W.
Published: February 2005

Developmental coordination is vital in the temporally coordinated appearance of cell types within the precise spatial architecture of the vertebrate brain and this, combined with the rich interplay between the developing brain and its target organs, is a biological problem of monumental complexity. An example is the genesis and subsequent integration of the neuroendocrine hypothalamus and the pituitary. Two recent papers(1,2) use the developing hypothalamo‐pituitary axis in order to gather a deeper understanding of these integrative mechanisms. In addition, they show that a sub‐family of homeodomain factors, the POU‐domain proteins, play a critical role in coordinating the respective ontogenies of the hypothalamus and the pituitary.
Simple sequences and the expanding genome
Authors: Hancock John M.
Published: February 2005

Recent analysis of the contribution of replication slippage to genome evolution shows that it has played a significant role in all species from eubacteria to humans. The overall level of repetition in genomes is related to genome size and to the degree of repetition that can be measured within individual ribosomai RNA genes, suggesting that the entire genome accepts simple sequences in a concerted manner when its size increases. Although coding sequences accept simple sequences much less readily than non‐coding sequences, they accept some repeats, particularly (CAG)n, preferentially. This may have consequences for the evolution of the genes involved in trinucleotide expansion diseases and the transcriptional networks of which they may form a part.
Genome analysis with gene expression microarrays
Authors: Schena Mark
Published: February 2005

Advances in biochemistry, chemistry and engineering have enabled the development of a new gene expression assay. This ‘chip‐based’ approach utilizes microscopic arrays of cDNAs printed on glass as high‐density hybridization targets. Fluorescent probe mixtures derived from total cellular messenger RNA (mRNA) hybridize to cognate elements on the array, allowing accurate measurement of the expression of the corresponding genes. Array densities of >1,000 cDNAs per cm2 enable quantitative expression monitoring of a large number of genes in a single hybridization. A two‐color fluorescence detection scheme allows rapid and simultaneous differential expression analysis of independent biological samples. Mass‐produced microarrays provide a new tool for genome expression analysis that may revolutionize genetic dissection, drug discovery and human disease diagnostics.
Electric fields at the plasma membrane level: A neglected element in the mechanisms of cell signalling
Authors: Olivotto Massimo , Arcangeli Annarosa , Carlà Marcello , Wanke Enzo
Published: February 2005

Membrane proteins possess certain features that make them susceptible to the electric fields generated at the level of the plasma membrane. A reappraisal of cell signalling, taking into account the protein interactions with the membrane electrostatic profile, suggests that an electrical dimension is deeply involved in this fundamental aspect of cell biology. At least three types of potentials can contribute to this dimension: (1) the potential across the compact layer of water adherent to membrane surfaces; this potential is affected by classical inducers of cell differentiation, like dimethylsulfoxide and hexamethylenebisacetamide; (2) the potential across the Gouy‐Chapman double layer, which accounts for the effects of extracellular cations in the modulation of differentiation; and (3) the resting potential. This last potential and its governing ion currents can be exploited in localised mechanisms of cell signalling centred on the functional association of integrin receptors with ion channels.
DNA filter elution: A window on DNA damage in mammalian cells
Authors: Kohn Kurt W.
Published: February 2005

This personal account traces a series of studies that led from DNA physical chemistry to anticancer drug mechanisms. Chemical crosslinking as a basis for anticancer drug actions had been suspected since the time of the first clinical reports of the effectiveness of nitrogen mustard in 1946. After the elucidation of the DNA helix‐coil transition, several nearly concurrent findings in the early 1960s established the paradigm of DNA interstrand crosslinking. The DNA filter elution phenomenon was discovered in the early 1970s, and lent itself to the development of practical assays for DNA crosslinks and other DNA lesions in mammalian cells. The assays allowed studies of the effects of DNA damaging agents at pharmacologically or toxicologically relevant doses, and have been widely applied in studies of mutagenic and chemotherapeutic agents. During the period 1979–1986, DNA filter elution studies led to the paradigm of DNA topoisomerases as targets of anticancer drug action, and this has become one of the most active areas of anticancer drug development.
Genomic imprinting in unstable DNA diseases
Authors: Petronis Arturas
Published: February 2005

Evidence for recombination suppression has been identified in linkage studies of several unstable DNA diseases. Also sex‐specific changes in recombination frequency have been detected at the loci of Huntington's disease and myotonic dystrophy. It can be hypothesized that meiotic recombination is regulated by genome‐wide genomic imprinting and that changes in meiotic recombination imply the presence of the genomic imprinting defect. If aberrant recombination at the locus of trinucleotide repeat expansion is verified, new theoretical and experimental opportunities will arise in studies on the role of genomic imprinting in the unstable DNA diseases.
Pattern formation: Regional specification in the early C. elegans embryo
Authors: Schnabel Ralf
Published: February 2005

Recent findings suggest that C. elegans, albeit displaying an invariant cell lineage for embryonic development, uses the same basic strategy for embryogenesis as other organisms. The early embryo is regionalised by cell‐cell interactions.
hnRNP particles
Authors: Samarina Olga P.
Published: February 2005

This article describes the discovery of nuclear DNA‐like RNA (dRNA or hnRNA) and ribonucleoprotein particles in eukaryotes. Native hnRNA particles were isolated by sucrose gradient sedimentation and their structural organisation – nucleic acid (i.e. RNA) wrapped in a regular way on the surface of a series of globular protein particles – was determined. This led to the formulation of the informofer cycle hypothesis for the synthesis of hnRNA as a giant precursor molecule, its transport in informosomes within the nucleus, and subsequent splicing before export from the nucleus as free mRNA.
The neutral theory is dead. Long live the neutral theory
Authors: Kreitman Martin
Published: February 2005

The neutral theory of molecular evolution has been instrumental in organizing our thinking about the nature of evolutionary forces shaping variation at the DNA level. More importantly, it has provided empiricists with a strong set of testable predictions and hence, a useful null hypothesis against which to test for the presence of selection. Evidence indicates that the neutral theory cannot explain key features of protein evolution nor patterns of biased codon usage in certain species. Whereas we now have a reasonable model of selection acting on synonymous changes inDrosophila, protein evolution remains poorly understood. Despite limitations in the applicability of the neutral theory, it is likely to remain an integral part of the quest to understand molecular evolution.
The coming of age of ventralising homeobox genes in amphibian development
Authors: Lemaire Patrick
Published: February 2005

The emerging view of early dorso‐ventral patterning of amphibian embryos is that two opposing gradients of dorsalising and ventralising secreted factors are necessary. while several transcription factors acting upstream or downstream of the dorsalising molecules have been identified, until recently little was known about the transcriptional response to ventralising signals. Now two groups describe the identification of related homeodomain proteins, Xvent‐1 and Vox, which are able to convert dorsal cells of Xenopus embryos into more ventral ones(1,2).
The roles of heterogeneous nuclear ribonucleoproteins (hnRNP) in RNA metabolism
Authors: Weighardt Florian , Biamonti Giuseppe , Riva Silvano
Published: February 2005

In eukaryotic cells, messenger RNAs are formed by extensive posttranscriptional processing of primary transcripts, assembled with a large number of proteins and processing factors in ribonucleoprotein complexes. The protein moiety of these complexes mainly constitutes a class of about 20 major polypeptides called heterogeneous nuclear ribonucleoproteins or hnRNPs. The function and the mechanism of action of hnRNPs is still not fully understood, but the identification of RNA binding domains and RNA binding specificities, and the development of new functional assays, has stimulated interest in them. In contrast to previous models that hypothesised a mere structural (histone‐like) function, a more diversified and dynamic role for these proteins is now emerging. In fact, they can be viewed as a subset of the trans‐acting pre‐mRNA maturation factors. They might actively participate in post‐transcriptional events such as regulated splicing and mRNA export. Moreover, recent data suggest an involvement of some of these proteins in molecular diseases. Here we present an overview of the most relevant properties of hnRNPs and discuss some emerging ideas on theiir roles.
Craniofacial defects in AP‐2 null mutant mice
Authors: Morriss‐Kay Gillian M.
Published: February 2005

AP‐2 is a recent significant addition to the list of transcription factors that have been demonstrated by targeted gene disruption to be essential for normal development. Two recent reports of AP‐2 null mutant mice(1,2) indicate that AP‐2 holds a key position in the network of genes and proteins controlling developmental pattern and morphogenesis, and that it is particularly important for development of the cranial region and for midline fusions.
Aging mechanisms in fruit flies
Authors: Tower John
Published: February 2005

Genetic analysis of Drosophil has provided evidence in support of two proposed evolutionary genetic mechanisms of aging: mutation accumulation and antagonistic pleiotropy. Both mechanisms result from the lack of natural selection acting on old organisms. Analyses of large numbers of flies have revealed that mortality rates do not continue to rise with age as previously thought, but plateau at advanced ages. This phenomenon has implications both for models and for definitions of aging, and may be explained by the evolutionary theories. The physiological processes and genes most relevant to aging are being identified using Drosophila lines selected in the laboratory for postponed senescence. Oxidative stress and insufficient metabolic reserves/capacity may be particularly important factors in limiting the fruitfly lifespan. Genes which exhibit aging‐related changes in expression are now being identified. Transgenic flies are being used to analyze the mechanisms of such aging‐related gene expression, and to test the effects of specific genes on aging and aging‐related deterioration.
X‐linked agammaglobulinemia (XLA): A genetic tyrosine kinase (Btk) disease
Authors: Mattsson Pekka T. , Vihinen Mauno , Smith C. I. Edvard
Published: February 2005

X‐linked agammaglobulinemia is a heritable immunodeficiency disease caused by a differentiation abnormality, resulting in the virtual absence of B Iymphocytes and plasma cells. The affected gene encodes a cytoplasmic protein tyrosine kinase, Bruton's agammaglobulinemia tyrosine kinase, designated Btk. Btk and the other family members, Tec, Itk and Bmx, contain five regions, four of which are common structural and functional modules that are found in other signaling proteins. Mutations affect all domains of the gene, but amino acid substitutions seem to be confined to certain regions. More than 150 unique mutations have been identified and are collected in a mutation database, BTKbase. Here we discuss the three‐dimensional structural implications of such mutations and their putative functional role. Of special interest are mutations affecting the pleckstrin homology domain, as Btk is the only disease‐associated protein so far reported to carry mutations in this particular module.
Asymmetry – where evolutionary and developmental genetics meet
Authors: Batterham Philip , Davies Andrew G. , Game Anne Y. , McKenzie John A.
Published: February 2005

The mechanisms responsible for the fine tuning of development, where the wildtype phenotype is reproduced with high fidelity, are not well understood. The difficulty in approaching this problem is the identification of mutant phenotypes indicative of a defect in these fine‐tuning control mechanisms. Evolutionary biologists have used asymmetry as a measure of developmental homeostasis. The rationale for this was that, since the same genome controls the development of the left and right sides of a bilaterally symmetrical organism, departures from symmetry can be used to measure genetic or environmental perturbations. This paper examines the relationship between asymmtry and resistance to organophosphorous insecticides in the Australian sheep blowfly, Lucilia cuprina. A resistance gene, Rop‐1, which encodes a carboxylesterase enzyme, also confers a significant increase in asymmetry. Continued exposure of resistant populations to insecticide has selected a dominant suppressor of the asymmetry phenotype. Genetic evidence indicates that the modifier is the L. cuprina Notch homologue.
Controlling growth of the wing: Vestigial integrates signals from the compartment boundaries
Authors: Cohen Stephen M.
Published: February 2005

In the past few years it has become apparent that the anterior/posterior (A/P) and dorsal/ventral (D/V) compartmant boundaries serve as the source of longrange signals that organize the A/P and D/V axes of the Drosophila wing. Recent work suggests that the vestigial gene may function as a nodal point through which the growth‐controlling activity of these two patterning systems is integrated(1).
Cdc6 and DNA replication: Limited to humble origins
Authors: Heichman Karen A.
Published: February 2005

The budding yeast Cdc6 protein is important for regulating DNA replication intiation. Cdc6p acts at replication origins, and cdc6‐1 mutants arrest with unreplicated DNA and show elevated minichromosome loss rates. Overexpression of the related Cdc 18 protein in fission yeast results in DNA rereplication; however, Cdc6p overexpression does not cause this result. A recent paper(1) further defines the role of Cdc6p in DNA replication. Cdc6p only promotes DNA replication between the end of mitosis and late G1, and although the Cdc6 protein is highly unstable, neither degradation nor nuclear localization is critical for limiting DNA replication to this interval.
Obesity genes and the regulation of body fat content
Authors: Weigle David S. , Kuijper Joseph L.
Published: February 2005

Physiological investigation has demonstrated that the central nervous system monitors body composition and adjusts energy intake and expenditure to stabilize total adipose tissue mass. Genetic variations in the signalling molecules involved in this regulatory system account for the heritable component of body fat content. The application of molecular techniques to rodent models of Mendelian obesity has resulted in the characterization of five loci at which mutations produce an abnormal accumulation of body fat. The genes at these loci include agouti, which encodes a molecule that antagonizes the binding of alpha melanocyte‐stimulating hormone to its receptor; fat, which encodes carboxypeptidase E; tubby, which encodes a putative phosphodiesterase; obese, which encodes a circulating satiety protein; and diabetes, which encodes the receptor for the obese gene product. A more detailed understanding of the functional interrelationships of these genes should lead to important new insights into the causes and potential therapies for human obesity.
Adaptive mutation: A general phenomenon or special case?
Authors: Benson Spencer
Published: February 2005

A recent article by Galitski and Roth(1) characterizes adaptive reversion of chromosomal lac− mutations in Salmonella typhimurium LT2. Using a classical genetic approach they show that adaptive reversion, as characterized by the appearance of late revertant colonies, is an exception rather than a general phenomenon for reversion of nonsense, missense, frameshift and insertion mutations. For certain mutations, however, the number of late revertants exceeds the predicted number. These excess revertants suggest that adaptive mutability is applicable to chromosomal genes as well as to genetic changes involving F plasmids and lysogenic phages.
Signaling molecules in regenerating hydra
Authors: Galliot Brigitte
Published: February 2005

Ever since it was discovered in hydra, regeneration has remained a stimulating question for developmental biologists. Cellular approaches have revealed that, within the first few hours of apical or basal hydra regeneration, differentiation and determination of nerve cells are the primary cellular events detectable. The head and foot activators (HA, FA), neuropeptides that are released upon injury, are signaling molecules involved in these processes. In conditions where it induces cellular differentiation or determination, HA behaves as an agonist of the cyclic AMP (cAMP) pathway involving the modulation of CREB nuclear transcription factor activity. This cascade would be required for proper regeneration, regardless of whether the polarity involved is apical or basal. Modulations of the protein kinase C pathway, which have been shown to affect apical or basal positional values, might signal to bring about this polarity; however, endogenous ligands responsible for this modulation are as yet unknown.
Fish technology in chromosome and genome research
Authors: Heng Henry H. Q. , Spyropoulos Barbara , Moens Peter B.
Published: February 2005

Fluorescent in situ hybridization technology is one of the most exciting and versatile research tools to be developed in recent years. It has enabled research to progress at a phenomenal rate in diverse areas of basic research as well as in clinical medicine. Fluorescent in situ hybridization has applications in physical mapping, the study of nuclear architecture and chromatin packaging, and the investigation of fundamental principles of biology such as DNA replication, RNA processing, gene amplification, gene integration and chromatin elimination. This review highlights some of these areas and provides source material for the reader who seeks more information on a specific field.
A proposed refinement of the mitochondrial free radical theory of aging
Authors: De Grey Aubrey D. N. J.
Published: February 2005

Over recent years, evidence has been accumulating in favour of the free radical theory of aging, first proposed by Harman. Despite this, an understanding of the mechanism by which cells might succumb to the effects of free radicals has proved elusive. This paper proposes such a mechanism, based on a previously unexplored hypothesis for the proliferation of mutant mitochondrial DNA: that mitochondria with reduced respiratory function, due to a mutation or deletion affecting the respiratory chain, suffer less frequent lysosomal degradation, because they inflict free radical damage more slowly on their own membranes. Once such a mutation occurs in a mitochondrion of a non‐dividing cell, therefore, mitochondria carrying it will rapidly populate that cell, thereby destroying the cell's respiratory capability. The accumulation of cells that have undergone this transition results in aging at the organismal level. The consistency of the hypothesis with known facts is discussed, and technically feasible tests are suggested, of both the proposed mechanism and its overall contribution to mammalian aging.
Cell cycle checkpoints: Arresting progress in mitosis
Authors: Gorbsky Gary J.
Published: February 2005

Cell cycle arrest in M phase can be induced by the failure of a single chromosome to attach properly to the mitotic spindle. The same cell cycle checkpoint mediates M phase arrest when cells are treated with drugs that either disrupt or hyperstabilize spindle microtubules. Study of yeast mutants that fail to arrest in the presence of microtubule disruptors identified a set of genes important in this checkpoint pathway. Two recent papers report the cloning of human and Xenopus homologues of one of these yeast genes, called MAD2 (for mitotic arrest deficient‐2)(1,2). Introduction of antibodies to the MAD2 protein into living mammalian cells or Xenopus egg extracts abrogates the M phase arrest induced by microtubule inhibitors. This and other recent developments suggest a model for the M phase checkpoint in which unattached kinetochores inhibit the ubiquitination of proteins whose proteolysis is necessary for chromatid separation and exit from mitosis.
Functional differentiation of white and brown adipocytes
Authors: Klaus Susanne
Published: February 2005

Adipose tissue plays an important role in mammalian energy equilibrium not only as a lipid‐dissipating, i.e. energy‐storing, tissue (white adipose tissue), but also as an energy‐dissipating one (brown adipose tissue). Brown adipocytes have the ability of facultative heat production due to a unique mitochondrial protein, the uncoupling protein (UCP). Differentiation of white and (to a lesser extent) brown adipocytes has been studied in different cell culture systems, which has led to the identification of external inducers, second messenger pathways and transcription factors involved in adipocyte differentiation. Functional differentiation of white adipocytes implies adipose conversion, whereas in brown adipocytes it insinuates additionally the development of a thermogenic function. This review discusses recent advances in the elucidation of the pathways responsible for, and the molecular bases of, adipose conversion on the one hand and development of the thermogenic properties of brown adipocytes on the other.
The FEN‐1 family of structure‐specific nucleases in eukaryotic dna replication, recombination and repair
Authors: Lieber Michael R.
Published: February 2005

Unlike the most well‐characterized prokaryotic polymerase, E. Coli DNA pol I, none of the eukaryotic polymerases have their own 5′ to 3′ exonuclease domain for nick translation and Okazaki fragment processing. In eukaryotes, FEN‐1 is an endo‐and exonuclease that carries out this function independently of the polymerase molecules. Only seven nucleases have been cloned from multicellular eukaryotic cells. Among these, FEN‐1 is intriguing because it has complex structural preferences; specifically, it cleaves at branched DNA structures. The cloning of FEN‐1 permitted establishment of the first eukaryotic nuclease family, predicting that S. cerevisiae RAD2 (S. pombe Rad13) and its mammalian homolog, XPG, would have similar structural specficity. The FEN‐1 nuclease family includes several similar enzymes encoded by bacteriophages. The crystal structures of two enzymes in the FEN‐1 nuclease family have been solved and they provide a structural basis for the interesting steric requirements of FEN‐1 substrates. Because of their unique structural specificities, FEN‐1 and its family members have important roles in DNA replication, repair and, potentially, recombination. Recently, FEN‐1 was found to specifically associate with PCNA, explaining some aspects of FEN‐1 function during DNA replication and potentially in DNA repair.
Nip and tuck at the neuromuscular junction: A role for proteases in developmental synapse elimination
Authors: Chang Qiang , Balice‐Gordon Rita J.
Published: February 2005

During late embryonic and early postnatal development, synaptic connections are extensively modified so that some functional connections are weakened and eliminated from a neural circuit while others are strengthened and maintained. The mechanisms that underlie synapse elimination are beginning to be understood from studies of the neuromuscular junction. A recent paper(1) provides some intriguing insights into the role proteases may play in the developmental disassembly of neuromuscular synapses.
Cyclins, cyclin‐dependent kinases and differentiation
Authors: Gao Chun Y. , Zelenka Peggy S.
Published: February 2005

Cyclin‐dependent kinases and their regulatory subunits, the cyclins, are known to regulate progression through the cell cycle. Yet these same proteins are often expressed in non‐cycling, differentiated cells. This review surveys the available information about cyclins and cyclin‐dependent kinases in differentiated cells and explores the possibility that these proteins may have important functions that are independent of cell cycle regulation.
The pheromonal role of cuticular hydrocarbons in Drosophila melanogaster
Authors: Ferveur Jean‐François
Published: February 2005

Pheromones play a curcial role in mate stimulation and discrimination. In the fruit fly Drosophila, the most abundant cuticular hydrocarbons act as sex pheromones during courtship behavior. There are several active molecules and they compose a sex‐ and species‐specific pheromonal bouquet. Different species from the Drosophila melanogaster subgroup have adopted alternative systems of chemical mate recognition. Recent exploration of these interspecific variations, and of intraspecific variations, has led to the characterization of genes and to the mapping of structures that process the production and perception of chemical messages.
Telomeres, not the end of the story
Authors: Gotta Monica , Cockell Moira
Published: February 2005

Transcription in organisms as diverse as yeast and mammals is subject to chromosomal position effects that result in heritable and variegated patterns of gene expression. Two recent studies have employed a reversible protein‐DNA crosslinking method to identify the structural components of heterochromatin in budding yeast(1,2). The results show that a complex containing the proteins Rap1, Sir2p, Sir3p and Sir4p is physically associated with nucleosomes at telomere proximal regions, but that the repressive chromatin structure extended by Sir3p overexpression has a different composition.
The evolution of sex determination in isopod crustaceans
Authors: Rigaud Thierry , Juchault Pierre , Mocquard Jean‐Pierre
Published: February 2005

Sex is determined by non‐Mendelian genetic elements overriding the sex factors carried by the heterochromosomes in some species of terrestrial isopods. A bacterium Wolbachia and a non‐bacterial feminizing factor (f) can both force chromosomal males of Armadillidium vulgare to become phenotypic functional females. The f factor is believed to be a genetic element derived from the Wolbachia genome that becomes inserted into the host nuclear genome. The feminizing factors can be considered to be selfish genetic elements because they bias their host's sex ratio to increase their own transmission. New sex‐determining genes are selected (genes resisting the feminizing effects, or the transmission of feminizing elements) as a consequence of the conflict between these elements and the rest of the host's genome. These events drive the sex‐determining mechanisms to evolve, and may explain the polymorphism of sex factors and the poor differentiation of the heterochromosomes in isopods.