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PubMed2004

Intracellular bacterial communities of uropathogenic Escherichia coli in urinary tract pathogenesis.

Urinary tract infections in young, healthy women frequently recur, despite their traditional classification as acute infections. Conventional wisdom dictates that uropathogens causing recurrent infections in such individuals come from the fecal or vaginal flora, in the same manner as the initial infection. However, recent studies of uropathogenic Escherichia coli have found that it can carry out a complex developmental program within the superficial epithelial cells of the mouse bladder, forming intracellular bacterial communities with many biofilm-like properties. These intracellular biofilms allow the bacteria to outlast a strong host immune response to establish a dormant reservoir of pathogens inside the bladder cells. Re-emergence of bacteria from this reservoir might be the source of recurrent infection.

Animals↗

PubMed2003

Knowing when to grow: signals regulating bud dormancy.

Dormancy regulation in vegetative buds is a complex process necessary for plant survival, development and architecture. Our understanding of and ability to manipulate these processes are crucial for increasing the yield and availability of much of the world's food. In many cases, release of dormancy results in increased cell division and changes in developmental programs. Much can be learned about dormancy regulation by identifying interactions of signals in these crucial processes. Internal signals such as hormones and sugar, and external signals such as light act through specific, overlapping signal transduction pathways to regulate endo-, eco- and paradormancy. Epigenetic-like regulation of endodormancy suggests a possible role for chromatin remodeling similar to that known for the vernalization responses during flowering.

Carbohydrate Metabolism↗

PubMed2004

Myogenic defects in myotonic dystrophy.

Myogenesis is the developmental program that generates and regenerates skeletal muscle. This process is impaired in patients afflicted with myotonic dystrophy type 1 (DM1). Muscle development is disrupted in infants born with congenital DM1, and recent evidence suggests that defective regeneration may contribute to muscle weakness and wasting in affected adults. DM1 represents the first example of a human disease that is caused, at least in part, by pathogenic mRNA. Cell culture models have been used to demonstrate that mutant DM1 mRNA takes on a gain-of-function and inhibits myoblast differentiation. Although the molecular mechanism(s) by which this mutant mRNA disrupts myogenesis is not fully understood, recent findings suggest that anomalous RNA-protein interactions have downstream consequences that compromise key myogenic factors. In this review, we revisit morphological studies that revealed the nature of myogenic abnormalities seen in patients, describe cell culture systems that have been used to investigate this phenotype and discuss recent discoveries that for the first time have identified myogenic events that are disrupted in DM1.

Animals↗

PubMed2004

Distinguishing the contributions of the perichondrium, cartilage, and vascular endothelium to skeletal development.

During the initiation of endochondral ossification three events occur that are inextricably linked in time and space: chondrocytes undergo terminal differentiation and cell death, the skeletal vascular endothelium invades the hypertrophic cartilage matrix, and osteoblasts differentiate and begin to deposit a bony matrix. These developmental programs implicate three tissues, the cartilage, the perichondrium, and the vascular endothelium. Due to their intimate associations, the interactions among these three tissues are exceedingly difficult to distinguish and elucidate. We developed an ex vivo system to unlink the processes initiating endochondral ossification and establish more precisely the cellular and molecular contributions of the three tissues involved. In this ex vivo system, the renal capsule of adult mice was used as a host environment to grow skeletal elements. We first used a genetic strategy to follow the fate of cells derived from the perichondrium and from the vasculature. We found that the perichondrium, but not the host vasculature, is the source of both trabecular and cortical osteoblasts. Endothelial cells residing within the perichondrium are the first cells to participate in the invasion of the hypertrophic cartilage matrix, followed by endothelial cells derived from the host environment. We then combined these lineage analyses with a series of tissue manipulations to address how the absence of the perichondrium or the vascular endothelium affected skeletal development. We show that although the perichondrium influences the rate of chondrocytes maturation and hypertrophy, it is not essential for chondrocytes to undergo late hypertrophy. The perichondrium is crucial for the proper invasion of blood vessels into the hypertrophic cartilage and both the perichondrium and the vasculature are essential for endochondral ossification. Collectively, these studies clarify further the contributions of the cartilage, perichondrium, and vascular endothelium to long bone development.

Animals↗

PubMed2005

cDermo-1 misexpression induces dense dermis, feathers, and scales.

Reciprocal epithelio-mesenchymal interactions between the prospective epidermis and the underlying dermis are the major driving forces in the development of skin appendages. Feather development is initiated by a still unknown signal from the dermis in feather-forming skin. The morphological response of the ectoderm to this signal is the formation of an epidermal placode, which signals back to the mesenchyme to induce dermal condensations. Together, epidermal and dermal components constitute the outgrowing feather bud. The bHLH transcription factor cDermo-1 is expressed in developing dermis and is the earliest known marker of prospective feather tracts. To test its function during feather development, we forced cDermo-1 expression in embryonic chicken dermis using a retroviral expression vector. In featherless (apteric) regions, cDermo-1 misexpression induced dense, thickened dermis normally observed in feathered skin (pterylae), and leads to the development of regularly spaced and normally shaped ectopic feather buds. In pterylae, cDermo-1 misexpression enhanced feather growth. In hindlimb skin, according to the local skin identity, misexpression of cDermo-1 induced ectopic scale formation. Thus, we show that forced cDermo-1 expression in developing dermis is sufficient to launch the developmental program leading to skin appendage formation. We propose a role of cDermo-1 at the initial stages of feather induction upstream of FGF10.

Animals↗

PubMed2005

Ethanolamine kinase controls neuroblast divisions in Drosophila mushroom bodies.

The Drosophila mushroom bodies (MBs), paired brain structures composed of vertical and medial lobes, achieve their final organization at metamorphosis. The alpha lobe absent (ala) mutant randomly lacks either the vertical lobes or two of the median lobes. We characterize the ala axonal phenotype at the single-cell level, and show that the ala mutation affects Drosophila ethanolamine (Etn) kinase activity and induces Etn accumulation. Etn kinase is overexpressed in almost all cancer cells. We demonstrate that this enzymatic activity is required in MB neuroblasts to allow a rapid rate of cell division at metamorphosis, linking Etn kinase activity with mitotic progression. Tight control of the pace of neuroblast division is therefore crucial for completion of the developmental program in the adult brain.

Animals↗

PubMed2006

Patterning of the third pharyngeal pouch into thymus/parathyroid by Six and Eya1.

Previous studies have suggested a role of the homeodomain Six family proteins in patterning the developing vertebrate head that involves appropriate segmentation of three tissue layers, the endoderm, the paraxial mesoderm and the neural crest cells; however, the developmental programs and mechanisms by which the Six genes act in the pharyngeal endoderm remain largely unknown. Here, we examined their roles in pharyngeal pouch development. Six1-/- mice lack thymus and parathyroid and analysis of Six1-/- third pouch endoderm demonstrated that the patterning of the third pouch into thymus/parathyroid primordia is initiated. However, the endodermal cells of the thymus/parathyroid rudiments fail to maintain the expression of the parathyroid-specific gene Gcm2 and the thymus-specific gene Foxn1 and subsequently undergo abnormal apoptosis, leading to a complete disappearance of organ primordia by E12.5. This thus defines the thymus/parathyroid defects present in the Six1 mutant. Analyses of the thymus/parathyroid development in Six1-/-;Six4-/- double mutant show that both Six1 and Six4 act synergistically to control morphogenetic movements of early thymus/parathyroid tissues, and the threshold of Six1/Six4 appears to be crucial for the regulation of the organ primordia-specific gene expression. Previous studies in flies and mice suggested that Eya and Six genes may function downstream of Pax genes. Our data clearly show that Eya1 and Six1 expression in the pouches does not require Pax1/Pax9 function, suggesting that they may function independently from Pax1/Pax9. In contrast, Pax1 expression in all pharyngeal pouches requires both Eya1 and Six1 function. Moreover, we show that the expression of Tbx1, Fgf8 and Wnt5b in the pouch endoderm was normal in Six1-/- embryos and slightly reduced in Six1-/-;Six4-/- double mutant, but was largely reduced in Eya1-/- embryos. These results indicate that Eya1 appears to be upstream of very early events in the initiation of thymus/parathyroid organogenesis, while Six genes appear to act in an early differentiation step during thymus/parathyroid morphogenesis. Together, these analyses establish an essential role for Eya1 and Six genes in patterning the third pouch into organ-specific primordia.

Animals↗

PubMed2006

Chromatin modifications in the germinal vesicle (GV) of mammalian oocytes.

The nucleus of eukaryotic cells is organized into functionally specialized compartments that are essential for the control of gene expression, chromosome architecture and cellular differentiation. The mouse oocyte nucleus or germinal vesicle (GV) exhibits a unique chromatin configuration that is subject to dynamic modifications during oogenesis. This process of 'epigenetic maturation' is critical to confer the female gamete with meiotic as well as developmental competence. In spite of its biological significance, little is known concerning the cellular and molecular mechanisms regulating large-scale chromatin structure in mammalian oocytes. Here, recent findings that provide mechanistic insight into the complex relationship between large-scale chromatin structure and global transcriptional repression in pre-ovulatory oocytes will be discussed. Post-translational modifications of histone proteins such as acetylation and methylation are crucial for heterochromatin formation and thus play a key role in remodeling the oocyte genome. This strategy involves multiple and hierarchical chromatin modifications that regulate nuclear dynamics in response to a developmentally programmed signal(s), presumably of paracrine origin, before the resumption of meiosis. Models for the experimental manipulation of large-scale chromatin structure in vivo and in vitro will be instrumental to determine the key cellular pathways and oocyte-derived factors involved in genome-wide chromatin modifications. Importantly, analysis of the functional differentiation of chromatin structure in the oocyte genome with high resolution and in real time will have wide-ranging implications to understand the role of nuclear organization in meiosis, the events of nuclear reprogramming and the spatio-temporal regulation of gene expression during development and differentiation.

Animals↗

PubMed2006

Calmodulin-dependent protein kinase II triggers mouse egg activation and embryo development in the absence of Ca2+ oscillations.

Fertilization in mammalian eggs is accompanied by oscillatory changes in intracellular Ca(2+) concentration, which are critical for initiating and completing egg activation events and the developmental program. Ca(2+)/Camodulin-dependent protein kinase II (CaMKII) is a multifunctional enzyme that is postulated to be the downstream transducer of the Ca(2+) signal in many cell types. We tested the hypothesis that CaMKII is the major integrator of Ca(2+)-induced egg activation events and embryo development by microinjecting a cRNA that encodes a constitutively active (Ca(2+)-independent) mutant form of CaMKII (CA-CaMKII) into mouse eggs. Expression of this cRNA, which does not increase intracellular Ca(2+), induced a sustained rise in CaMKII activity and triggered egg activation events, including cell cycle resumption, and degradation and recruitment of maternal mRNAs; cortical granule exocytosis, however, did not occur normally. Furthermore, when mouse eggs were injected with sperm devoid of Ca(2+)-releasing activity and activated with either CA-CaMKII cRNA or by SrCl(2), similar rates and incidence of development to the blastocyst stage were observed. These results strongly suggest that CaMKII is a major integrator of the Ca(2+) changes that occur following fertilization.

Animals↗

PubMed2006

Laminar organization of the early developing anterior hypothalamus.

The bHLH-PAS transcription factor SIM1 is required for the development of neurons of the anterior hypothalamus (AH). In order to dissect this developmental program, we compared gene expression in the AH of E12.5 Sim1(+/+) and Sim1(-/-) littermates using an oligonucleotide-based microarray. Our analysis identified 48 genes that were downregulated and 8 genes that were upregulated. We examined the expression pattern of 10 of the identified genes--Cart, Cbln1, Alcam, Unc-13c, Rgs4, Lnx4, Irx3, Sax1, Ldb2 and Neurod6--by in situ hybridization in E12.5 embryos. All of these genes are expressed in domains that are contained within that of Sim1 and their expression is changed in Sim1(-/-) embryos as predicted by the microarray analysis. Classical dating studies have established that the hypothalamus follows an "outside-in" pattern of neurogenesis, with neurons of the lateral hypothalamus being born before the medial ones. Analysis of the genes identified in this microarray study showed that the developing AH is characterized by different layers of gene expression that most likely correspond to distinct waves of neurogenesis. In addition, our analysis suggests that Sim1 function is required for the production or the survival of postmitotic neurons as well as for correct positioning of AH neurons.

Animals↗

PubMed2006

IL4/PGE2 induction of an enlarged early endosomal compartment in mouse macrophages is Rab5-dependent.

The endosomal compartment and the plasma membrane form a complex partnership that controls signal transduction and trafficking of different molecules. The specificity and functionality of the early endocytic pathway are regulated by a growing number of Rab GTPases, particularly Rab5. In this study, we demonstrate that IL4 (a Th-2 cytokine) and prostaglandin E2 (PGE2) synergistically induce Rab5 and several Rab effector proteins, including Rin1 and EEA1, and promote the formation of an enlarged early endocytic (EEE) compartment. Endosome enlargement is linked to a substantial induction of the mannose receptor (MR), a well-characterized macrophage endocytic receptor. Both MR levels and MR-mediated endocytosis are enhanced approximately 7-fold. Fluid-phase endocytosis is also elevated in treated cells. Light microscopy and fractionation studies reveal that MR colocalizes predominantly with Rab5a and partially with Rab11, an endosomal recycling pathway marker. Using retroviral expression of Rab5a:S34N, a dominant negative mutant, and siRNA Rab5a silencing, we demonstrate that Rab5a is essential for the large endosome phenotype and for localization of MR in these structures. We speculate that the EEE is maintained by activated Rab5, and that the EEE phenotype is part of some macrophage developmental program such as cell fusion, a characteristic of IL4-stimulated cells.

Animals↗

PubMed2002

Candida commensalism and virulence: the evolution of phenotypic plasticity.

Candida albicans and related species live as benign commensals in one or more body locations in a majority of healthy individuals. As opportunistic pathogens, they are poised to overgrow cavities and penetrate tissue in response to an alteration in host physiology that presumably compromises the immune functions that normally suppress their growth. There is little evidence of the emergence of successful drug-resistant or hypervirulent strains that predominate in either the commensal or disease states. It appears more likely that all strains possess similar capabilities for rapid adaptation to drug therapy, the immune response and changes in body location and in host physiology. It is suggested that the mechanisms for rapid adaptation lie in the developmental programs of the bud-hypha transition and high frequency phenotypic switching, and in the modulation of the expression of virulence genes in response to environmental cues.

Adult↗

PubMed2003

Variations in ATM protein expression during normal lymphoid differentiation and among B-cell-derived neoplasias.

The ataxia telangiectasia mutated (ATM) protein plays a central role in the cellular response to DNA double-strand breaks (DSBs). Developmentally programmed DSBs are restricted to cellular subsets within lymphoid tissues and we asked whether ATM expression is differentially regulated during lymphoid differentiation. We showed that immature B cells in bone marrow and immature T cells of the thymic cortex were negative or weakly ATM-positive. T cells of thymic medulla and peripheral tissues strongly expressed ATM. High levels of ATM were present in the B lymphocytes of the mantle zone and in plasma cells, while the majority of germinal center B cells were negative or weakly labeled. Therefore, ATM expression appears to be down-regulated at those stages of lymphoid development where physiological DNA DSBs occur. In B-chronic lymphocytic leukemia and mantle cell lymphoma we observed two categories: ATM-negative tumors, most likely reflecting the presence of ATM mutation, and tumors with abundant ATM expression. Most follicular center-cell lymphomas and diffuse large B-cell lymphomas, which rarely show inactivation of the ATM gene, were negative or weakly ATM-positive. Tumor cells from most cases of Hodgkin's disease were ATM-negative. Therefore, unless ATM inactivation occurs, ATM expression in lymphoid tumors is likely to reflect their cellular origin. As a result, immunostaining to identify lymphoid neoplasias with ATM inactivation might only be feasible for tumors derived from the stages where ATM is constitutively highly expressed.

Antibodies, Monoclonal↗

PubMed1999

Identification of amino acids responsible for the oxygen sensitivity of ferredoxins from Anabaena variabilis using site-directed mutagenesis.

The filamentous cyanobacterium Anabaena variabilis (ATCC 29413) possesses two molybdenum dependent nitrogenase systems, nif1 and nif2. The nif1 system is regulated by a developmental program involving heterocyst differentiation; the nif2 system is expressed in all cells only under anaerobic conditions and the expression is controlled environmentally. The genes fdxH1 and fdxH2, encoding two [2Fe-2S] ferredoxins, are part of the these two distinct and differently regulated nif gene clusters. The sensitivity of both ferredoxins to oxygen was different; the half-life of FdxH2 in air was only approximately 1.5 h, while FdxH1 retained 80% of its nitrogenase activity after 24 h. We used site-directed mutagenesis to identify the role of individual amino acid residues responsible for oxygen sensitivity and found out that the FdxH2 double mutant I76A/V77L was much more resistant to oxygen than the wild-type ferredoxin (FdxH2) and similar to FdxH1. By modelling it was shown that the accessibility of the cavity around the iron-sulfur cluster was responsible for that.

Alanine↗

PubMed1988

Deletion of a homeobox gene in myeloid leukemias with a deletion in chromosome 2.

Mouse myeloid leukemias are characterized by a frequent deletion in one chromosome number 2. We now show that there is a deletion of one copy of the Hox-4.1 homeobox gene in the myeloid leukemias with this deletion in chromosome 2. It is suggested that deletion of this homeobox gene plays a role in determining the abnormal developmental program in myeloid leukemia.

Animals↗

PubMed2000

Effects of transient ethanol exposure on the incorporation of [(3)H]ethanolamine into plasmalogen in the differentiating CG-4 oligodendrocyte cell line.

We investigated the potential teratogenic effects of ethanol (EtOH) on myelination by monitoring its effects on the labeling of the myelin-typical lipid, ethanolamine plasmalogen (EPl), in the CG-4 cell line of differentiating oligodendrocytes (OLGs). On 5 different days during the first 8 days of OLG development, cells were labeled for 24 hr with [(3)H]ethanolamine to label EPl and diacyl-ethanolamine phosphoglycerols (diacyl-EPG), and the amount of labeled lipid expressed on each day was determined in the presence and absence of 25-120 mM EtOH. At early stages of development, a lower amount of [(3)H]EPl per cell was found in cells exposed to EtOH. The ratio of [(3)H]EPl to [(3)H]diacyl-EPG in cells exposed to 25, 50, or 120 mM EtOH was decreased by 50% after 4 days of differentiation compared with that in control cells. By adding or withdrawing EtOH at specific days of differentiation, we showed that EtOH inhibited the increased labeling of EPl if it was present for the first 48 hr of differentiation, and subsequent withdrawal failed to relieve the inhibition. Addition of EtOH anytime after the first day of differentiation did not inhibit the increased labeling of EPl. The results show that the increased labeling of EPl in differentiating OLGs resulted from an EtOH-sensitive, developmentally programmed, transient process active only during the first 2 days of differentiation.

Animals↗

PubMed1998

Regulation of cellular and system function by activin.

Activin is an important molecule that regulates hormonogenesis, cellular homeostasis (divide or die pathways), and differentiation programs (developmentally and in adult cells). The cellular mechanisms that integrate an activin signal into a physiological response include a binary receptor complex and tandem serine threonine kinases, intracellular signal mediators, and nuclear transcription factors. Activin antagonists (inhibins) and bioneutralizing binding proteins (follistatins) act as gating molecules to ensure accurate delivery of activin signals to cellular machinery. Correct execution of an activin cue intracellularly permits actions as fundamental as embryonic mesoderm development, neuronal survival, hematopoietic function, and reproductive cyclicity. Absent or incorrect activin signaling results in phenotypes as catastrophic as embryonic lethality, tumor formation, and infertility. The general ways in which a cell senses and responds to an activin signal will be reviewed in the first part of this paper. The role of this ligand in reproductive function will also be examined as a specific example of activin activity.

Activins↗

PubMed2002

Prenatal protein malnutrition decreases mossy fibers-CA3 thorny excrescences asymmetrical synapses in adult rats.

Prenatal protein malnutrition has deleterious effects on hippocampal structure and function that likely result from decreased synapse number. We thus evaluated long-term effects of prenatal protein malnutrition on the mossy fibers-CA3 thorny excrescences asymmetrical synapses in 220-day-old rats. Protein malnourished rats born from pregnant dams fed with 6% casein diet were cross-fostered to lactating control rats at birth. Control animals were fed with a 25% casein diet. Timm's stained material was used to estimate the total reference volume of the mossy fiber system suprapyramidal bundle by means of stereology. The mossy fiber-CA3 asymmetrical synapse numerical density was obtained by electron microscopy, using the physical disector method. The total number of mossy fiber-CA3 asymmetrical synapses was determined on the basis of the total reference volume of the mossy fiber system suprapyramidal bundle and the mossy fiber-CA3 asymmetrical synapse numerical density. Prenatal protein malnutrition produced long-lasting, significant decreases in the volume of the mossy fiber system suprapyramidal bundle and in the numerical density of mossy fiber-CA3 asymmetrical synapse, suggesting a reduction in the total number of this synapse type. Hence, prenatal protein malnutrition induces long lasting deleterious effects on the progression of developmental programs controlling synaptogenesis and/or synaptic consolidation, likely by affecting a myriad of cellular processes.

Animals↗