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‣ Molecular mechanisms underlying the regulation of brain-derived neurotrophic factor (BDNF) translation in dendrites

Pinheiro, Vera Lúcia Margarido
Fonte: Universidade de Coimbra Publicador: Universidade de Coimbra
Tipo: Dissertação de Mestrado
Português
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491.60664%
A especificidade espacial e temporal subjacente à diversidade de processos de plasticidade sináptica que ocorrem no sistema nervoso central está profundamente relacionada com a disponibilidade da proteína brain-derived neurotrophic factor (BDNF) em domínios sub-celulares distintos, especialmente na área pós-sináptica. Contudo, os mecanismos moleculares que regulam a síntese proteica de BDNF nas dendrites estão ainda por desvendar. Assim, o principal objectivo deste trabalho foi investigar alguns dos mecanismos de regulação da síntese de BDNF em diferentes regiões das dendrites. Em particular, foram estudados os mecanismos envolvidos na regulação dos níveis de BDNF em resposta à estimulação eléctrica in vitro e a um estímulo epileptogénico in vivo, e a contribuição da maquinaria de síntese proteica para essas alterações. Usando imunocitoquímica demonstrámos que o aumento dos níveis da proteína BDNF resultante da actividade neuronal está dependente da acção de alguns elementos no processo de síntese proteica. Em particular, a proteína ribossomal S6 parece ter um papel preponderante nas fases iniciais da tradução, enquanto a cinase de proteínas Aurora A, envolvida em mecanismos de tradução dependentes de 3’UTR...

‣ Molecular Mechanism of the Bifunctional Role of Lipopolysaccharide in Osteoclastogenesis*

Liu, Jianzhong; Wang, Shunqing; Zhang, Ping; Said-Al-Naief, Nasser; Michalek, Suzanne M.; Feng, Xu
Fonte: American Society for Biochemistry and Molecular Biology Publicador: American Society for Biochemistry and Molecular Biology
Tipo: Artigo de Revista Científica
Publicado em 01/05/2009 Português
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562.21133%
Lipopolysaccharide (LPS), a common bacteria-derived product, has long been recognized as a key factor implicated in periodontal bone loss. However, the precise cellular and molecular mechanisms by which LPS induces bone loss still remains controversial. Here, we show that LPS inhibited osteoclastogenesis from freshly isolated osteoclast precursors but stimulated osteoclast formation from those pretreated with RANKL in vitro in tissue culture dishes, bone slices, and a co-culture system containing osteoblasts, indicating that RANKL-mediated lineage commitment is a prerequisite for LPS-induced osteoclastogenesis. Moreover, the RANKL-mediated lineage commitment is long term, irreversible, and TLR4-dependent. LPS exerts the dual function primarily by modulating the expression of NFATc1, a master regulator of osteoclastogenesis, in that it abolished RANKL-induced NFATc1 expression in freshly isolated osteoclast precursors but stimulated its expression in RANKL-pretreated cells. In addition, LPS prolonged osteoclast survival by activating the Akt, NF-κB, and ERK pathways. Our current work has not only unambiguously defined the role of LPS in osteoclastogenesis but also has elucidated the molecular mechanism underlying its complex functions in osteoclast formation and survival...

‣ Wiring Olfaction: The Cellular and Molecular Mechanisms that Guide the Development of Synaptic Connections from the Nose to the Cortex

de Castro, Fernando
Fonte: Frontiers Research Foundation Publicador: Frontiers Research Foundation
Tipo: Artigo de Revista Científica
Publicado em 04/12/2009 Português
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Within the central nervous system, the olfactory system fascinates by its developmental and physiological particularities, and is one of the most studied models to understand the mechanisms underlying the guidance of growing axons to their appropriate targets. A constellation of contact-mediated (laminins, CAMs, ephrins, etc.) and secreted mechanisms (semaphorins, slits, growth factors, etc.) are known to play different roles in the establishment of synaptic interactions between the olfactory epithelium, olfactory bulb (OB) and olfactory cortex. Specific mechanisms of this system (including the amazing family of about 1000 different olfactory receptors) have been also proposed. In the last years, different reviews have focused in partial sights, specially in the mechanisms involved in the formation of the olfactory nerve, but a detailed review of the mechanisms implicated in the development of the connections among the different olfactory structures (olfactory epithelium, OB, olfactory cortex) remains to be written. In the present work, we afford this systematic review: the different cellular and molecular mechanisms which rule the formation of the olfactory nerve, the lateral olfactory tract and the intracortical connections, as well as the few data available regarding the accessory olfactory system. These mechanisms are compared...

‣ Monoamine Oxidase A Expression Is Vital for Embryonic Brain Development by Modulating Developmental Apoptosis*

Wang, Chi Chiu; Borchert, Astrid; Ugun-Klusek, Aslihan; Tang, Ling Yin; Lui, Wai Ting; Chu, Ching Yan; Billett, Ellen; Kuhn, Hartmut; Ufer, Christoph
Fonte: American Society for Biochemistry and Molecular Biology Publicador: American Society for Biochemistry and Molecular Biology
Tipo: Artigo de Revista Científica
Português
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470.58227%
Monoamine oxidases (MAO-A, MAO-B) metabolize biogenic amines and have been implicated in neuronal apoptosis. Although apoptosis is an important process in embryo development, the role of MAO isoenzymes has not been investigated in detail. We found that expression of MAO-A and MAO-B can be detected early on during embryo development. Expression levels remained constant until around midgestation but then dropped to almost undetectable levels toward birth. Similar expression kinetics were observed in the brain. Isoform-specific expression silencing of MAO-A mediated by siRNA during in vitro embryogenesis induced developmental defects, as indicated by a reduction of the crown rump length and impaired cerebral development. These alterations were paralleled by elevated serotonin levels. Similar abnormalities were observed when embryos were cultured in the presence of the MAO-A inhibitor clorgyline or when the transcriptional inhibitor of MAO-A expression R1 was overexpressed. In contrast, no such alterations were detected when expression of MAO-B was knocked down. To explore the underlying mechanisms for the developmental abnormalities in MAO-A knockdown embryos, we quantified the degree of developmental apoptosis in the developing brain. MAO-A knockdown reduced the number of apoptotic cells in the neuroepithelium...

‣ Proteome Analysis of Distinct Developmental Stages of Human Natural Killer (NK) Cells

Scheiter, Maxi; Lau, Ulrike; van Ham, Marco; Bulitta, Björn; Gröbe, Lothar; Garritsen, Henk; Klawonn, Frank; König, Sebastian; Jänsch, Lothar
Fonte: The American Society for Biochemistry and Molecular Biology Publicador: The American Society for Biochemistry and Molecular Biology
Tipo: Artigo de Revista Científica
Português
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The recent Natural Killer (NK) cell maturation model postulates that CD34+ hematopoietic stem cells (HSC) first develop into CD56bright NK cells, then into CD56dimCD57− and finally into terminally maturated CD56dimCD57+. The molecular mechanisms of human NK cell differentiation and maturation however are incompletely characterized. Here we present a proteome analysis of distinct developmental stages of human primary NK cells, isolated from healthy human blood donors. Peptide sequencing was used to comparatively analyze CD56bright NK cells versus CD56dim NK cells and CD56dimCD57− NK cells versus CD56dimCD57+ NK cells and revealed distinct protein signatures for all of these subsets. Quantitative data for about 3400 proteins were obtained and support the current differentiation model. Furthermore, 11 donor-independently, but developmental stage specifically regulated proteins so far undescribed in NK cells were revealed, which may contribute to NK cell development and may elucidate a molecular source for NK cell effector functions.

‣ Evolution of the fruit endocarp: molecular mechanisms underlying adaptations in seed protection and dispersal strategies

Dardick, Chris; Callahan, Ann M.
Fonte: Frontiers Media S.A. Publicador: Frontiers Media S.A.
Tipo: Artigo de Revista Científica
Publicado em 25/06/2014 Português
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Plant evolution is largely driven by adaptations in seed protection and dispersal strategies that allow diversification into new niches. This is evident by the tremendous variation in flowering and fruiting structures present both across and within different plant lineages. Within a single plant family a staggering variety of fruit types can be found such as fleshy fruits including berries, pomes, and drupes and dry fruit structures like achenes, capsules, and follicles. What are the evolutionary mechanisms that enable such dramatic shifts to occur in a relatively short period of time? This remains a fundamental question of plant biology today. On the surface it seems that these extreme differences in form and function must be the consequence of very different developmental programs that require unique sets of genes. Yet as we begin to decipher the molecular and genetic basis underlying fruit form it is becoming apparent that simple genetic changes in key developmental regulatory genes can have profound anatomical effects. In this review, we discuss recent advances in understanding the molecular mechanisms of fruit endocarp tissue differentiation that have contributed to species diversification within three plant lineages.

‣ Genomewide Analysis of PRC1 and PRC2 Occupancy Identifies Two Classes of Bivalent Domains

Rheinbay, Esther; Endoh, Mitsuhiro; Mikkelsen, Tarjei S.; Nusbaum, Chad; Xie, Xiaohui; Adli, Mazhar; Kasif, Simon; Ptaszek, Leon M.; Koseki, Haruhiko; van Steensel, Bas; Ku, Manching; Koche, Richard Patrick; Mendenhall, Eric M; Presser, Aviva; Chi, Andrew
Fonte: Public Library of Science Publicador: Public Library of Science
Tipo: Artigo de Revista Científica
Português
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470.56547%
In embryonic stem (ES) cells, bivalent chromatin domains with overlapping repressive (H3 lysine 27 tri-methylation) and activating (H3 lysine 4 tri-methylation) histone modifications mark the promoters of more than 2,000 genes. To gain insight into the structure and function of bivalent domains, we mapped key histone modifications and subunits of Polycomb-repressive complexes 1 and 2 (PRC1 and PRC2) genomewide in human and mouse ES cells by chromatin immunoprecipitation, followed by ultra high-throughput sequencing. We find that bivalent domains can be segregated into two classes—the first occupied by both PRC2 and PRC1 (PRC1-positive) and the second specifically bound by PRC2 (PRC2-only). PRC1-positive bivalent domains appear functionally distinct as they more efficiently retain lysine 27 tri-methylation upon differentiation, show stringent conservation of chromatin state, and associate with an overwhelming number of developmental regulator gene promoters. We also used computational genomics to search for sequence determinants of Polycomb binding. This analysis revealed that the genomewide locations of PRC2 and PRC1 can be largely predicted from the locations, sizes, and underlying motif contents of CpG islands. We propose that large CpG islands depleted of activating motifs confer epigenetic memory by recruiting the full repertoire of Polycomb complexes in pluripotent cells.; Stem Cell and Regenerative Biology

‣ All-Trans Retinoic Acid Directs Urothelial Specification of Murine Embryonic Stem Cells via GATA4/6 Signaling Mechanisms

Mauney, Joshua Robert; Ramachandran, Aruna; Yu, Richard N.; Daley, George Quentin; Adam, Rosalyn Mare; Estrada, Carlos R.
Fonte: Public Library of Science Publicador: Public Library of Science
Tipo: Artigo de Revista Científica
Português
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567.3571%
The urinary bladder and associated tract are lined by the urothelium, a transitional epithelium that acts as a specialized permeability barrier that protects the underlying tissue from urine via expression of a highly specific group of proteins known as the uroplakins (UP). To date, our understanding of the developmental processes responsible for urothelial differentiation has been hampered due to the lack of suitable models. In this study, we describe a novel in vitro cell culture system for derivation of urothelial cells from murine embryonic stem cells (ESCs) following cultivation on collagen matrices in the presence all trans retinoic acid (RA). Upon stimulation with micromolar concentrations of RA, ESCs significantly downregulated the pluripotency factor OCT-4 but markedly upregulated UP1A, UP1B, UP2, UP3A, and UP3B mRNA levels in comparison to naïve ESCs and spontaneously differentiating controls. Pan-UP protein expression was associated with both p63- and cytokeratin 20-positive cells in discrete aggregating populations of ESCs following 9 and 14 days of RA stimulation. Analysis of endodermal transcription factors such as GATA4 and GATA6 revealed significant upregulation and nuclear enrichment in RA-treated UP2-GFP+ populations. GATA4−/− and GATA6−/− transgenic ESC lines revealed substantial attenuation of RA-mediated UP expression in comparison to wild type controls. In addition...

‣ Functional Evolution of cis-Regulatory Modules at a Homeotic Gene in Drosophila

Ho, Margaret C. W.; Goetz, Sara E.; Schiller, Benjamin J.; Bae, Esther; Tran, Diana A.; Shur, Andrey S.; Rau, Christoph; Celniker, Susan E.; Drewell, Robert A.; Johnsen, Holly; Allen, John M; Bender, Welcome W.; Fisher, William W.
Fonte: Public Library of Science Publicador: Public Library of Science
Tipo: Artigo de Revista Científica
Português
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It is a long-held belief in evolutionary biology that the rate of molecular evolution for a given DNA sequence is inversely related to the level of functional constraint. This belief holds true for the protein-coding homeotic (Hox) genes originally discovered in Drosophila melanogaster. Expression of the Hox genes in Drosophila embryos is essential for body patterning and is controlled by an extensive array of cis-regulatory modules (CRMs). How the regulatory modules functionally evolve in different species is not clear. A comparison of the CRMs for the Abdominal-B gene from different Drosophila species reveals relatively low levels of overall sequence conservation. However, embryonic enhancer CRMs from other Drosophila species direct transgenic reporter gene expression in the same spatial and temporal patterns during development as their D. melanogaster orthologs. Bioinformatic analysis reveals the presence of short conserved sequences within defined CRMs, representing gap and pair-rule transcription factor binding sites. One predicted binding site for the gap transcription factor KRUPPEL in the IAB5 CRM was found to be altered in Superabdominal (Sab) mutations. In Sab mutant flies, the third abdominal segment is transformed into a copy of the fifth abdominal segment. A model for KRUPPEL-mediated repression at this binding site is presented. These findings challenge our current understanding of the relationship between sequence evolution at the molecular level and functional activity of a CRM. While the overall sequence conservation at Drosophila CRMs is not distinctive from neighboring genomic regions...

‣ Dorsomorphin, a Selective Small Molecule Inhibitor of BMP Signaling, Promotes Cardiomyogenesis in Embryonic Stem Cells

Hao, Jijun; Daleo, Marie A.; Murphy, Clare K.; Hu, Jianyong; Hatzopoulos, Antonis K.; Hong, Charles C.; Yu, Paul B.; Ho, Joshua N.; Peterson, Randall Theodore
Fonte: Public Library of Science Publicador: Public Library of Science
Tipo: Artigo de Revista Científica
Português
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474.79613%
Background: Pluripotent embryonic stem (ES) cells, which have the capacity to give rise to all tissue types in the body, show great promise as a versatile source of cells for regenerative therapy. However, the basic mechanisms of lineage specification of pluripotent stem cells are largely unknown, and generating sufficient quantities of desired cell types remains a formidable challenge. Small molecules, particularly those that modulate key developmental pathways like the bone morphogenetic protein (BMP) signaling cascade, hold promise as tools to study in vitro lineage specification and to direct differentiation of stem cells toward particular cell types. Methodology/Principal Findings: We describe the use of dorsomorphin, a selective small molecule inhibitor of BMP signaling, to induce myocardial differentiation in mouse ES cells. Cardiac induction is very robust, increasing the yield of spontaneously beating cardiomyocytes by at least 20 fold. Dorsomorphin, unlike the endogenous BMP antagonist Noggin, robustly induces cardiomyogenesis when treatment is limited to the initial 24-hours of ES cell differentiation. Quantitative-PCR analyses of differentiating ES cells indicate that pharmacological inhibition of BMP signaling during the early critical stage promotes the development of the cardiomyocyte lineage...

‣ Novel Secretion Apparatus Maintains Spore Integrity and Developmental Gene Expression in Bacillus subtilis

Doan, Thierry; Morlot, Cecile; Meisner, Jeffrey; Serrano, Monica; Henriques, Adriano O.; Rudner, David Z.; Moran, Charles P. Jr.
Fonte: Public Library of Science Publicador: Public Library of Science
Tipo: Artigo de Revista Científica
Português
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573.39938%
Sporulation in Bacillus subtilis involves two cells that follow separate but coordinately regulated developmental programs. Late in sporulation, the developing spore (the forespore) resides within a mother cell. The regulation of the forespore transcription factor σG that acts at this stage has remained enigmatic. σG activity requires eight mother-cell proteins encoded in the spoIIIA operon and the forespore protein SpoIIQ. Several of the SpoIIIA proteins share similarity with components of specialized secretion systems. One of them resembles a secretion ATPase and we demonstrate that the ATPase motifs are required for σG activity. We further show that the SpoIIIA proteins and SpoIIQ reside in a multimeric complex that spans the two membranes surrounding the forespore. Finally, we have discovered that these proteins are all required to maintain forespore integrity. In their absence, the forespore develops large invaginations and collapses. Importantly, maintenance of forespore integrity does not require σG. These results support a model in which the SpoIIIA-SpoIIQ proteins form a novel secretion apparatus that allows the mother cell to nurture the forespore, thereby maintaining forespore physiology and σG activity during spore maturation.

‣ Developmental Controls are Re-Expressed during Induction of Neurogenesis in the Neocortex of Young Adult Mice

Sohur, Usharbudh Shivraj; Arlotta, Paola; Macklis, Jeffrey Daniel
Fonte: Frontiers Research Foundation Publicador: Frontiers Research Foundation
Tipo: Artigo de Revista Científica
Português
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581.05555%
Whether induction of low-level neurogenesis in normally non-neurogenic regions of the adult brain mimics aspects of developmental neurogenesis is currently unknown. Previously, we and others identified that biophysically induced, neuron subtype-specific apoptosis in mouse neocortex results in induction of neurogenesis of limited numbers of subtype-appropriate projection neurons with axonal projections to either thalamus or spinal cord, depending on the neuron subtype activated to undergo targeted apoptosis. Here, we test the hypothesis that developmental genes from embryonic corticogenesis are re-activated, and that some of these genes might underlie induction of low-level adult neocortical neurogenesis. We directly investigated this hypothesis via microarray analysis of microdissected regions of young adult mouse neocortex undergoing biophysically activated targeted apoptosis of neocortical callosal projection neurons. We compared the microarray results identifying differentially expressed genes with public databases of embryonic developmental genes. We find that, following activation of subtype-specific neuronal apoptosis, three distinct sets of normal developmental genes are selectively re-expressed in neocortical regions of induced neurogenesis in young adult mice: (1) genes expressed by subsets of progenitors and immature neurons in the developing ventricular and/or subventricular zones; (2) genes normally expressed by developmental radial glial progenitors; and (3) genes involved in synaptogenesis. Together with previous results...

‣ Two developmental modules establish 3D beak-shape variation in Darwin's finches

Mallarino, Ricardo; Grant, P. R.; Grant, B. R.; Herrel, Antony; Kuo, W. P.; Abzhanov, Arkhat
Fonte: Proceedings of the National Academy of Sciences Publicador: Proceedings of the National Academy of Sciences
Tipo: Artigo de Revista Científica
Português
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471.96223%
Bird beaks display tremendous variation in shape and size, which is closely associated with the exploitation of multiple ecological niches and likely played a key role in the diversification of thousands of avian species. Previous studies have demonstrated some of the molecular mechanisms that regulate morphogenesis of the prenasal cartilage, which forms the initial beak skeleton. However, much of the beak diversity in birds depends on variation in the premaxillary bone. It forms later in development and becomes the most prominent functional and structural component of the adult upper beak/jaw, yet its regulation is unknown. Here, we studied a group of Darwin's finch species with different beak shapes. We found that TGFβIIr, β-catenin, and Dickkopf-3, the top candidate genes from a cDNA microarray screen, are differentially expressed in the developing premaxillary bone of embryos of species with different beak shapes. Furthermore, our functional experiments demonstrate that these molecules form a regulatory network governing the morphology of the premaxillary bone, which differs from the network controlling the prenasal cartilage, but has the same species-specific domains of expression. These results offer potential mechanisms that may explain how the tightly coupled depth and width dimensions can evolve independently. The two-module program of development involving independent regulating molecules offers unique insights into how different developmental pathways may be modified and combined to induce multidimensional shifts in beak morphology. Similar modularity in development may characterize complex traits in other organisms to a greater extent than is currently appreciated.; Organismic and Evolutionary Biology

‣ Molecular mechanisms by which T-bet regulates T-helper cell commitment

Miller, Sara A.; Weinmann, Amy S.
Fonte: PubMed Publicador: PubMed
Tipo: Artigo de Revista Científica
Publicado em /11/2010 Português
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470.5234%
Current research suggests that a number of newly identified helper T-cell subsets retain a degree of context-dependent plasticity in their signature cytokine expression patterns. To understand this process, a major challenge is to determine the molecular mechanisms by which lineage-defining transcription factors regulate gene expression profiles in helper T cells. This mechanistic information will aid in our interpretation of whether a T-helper cell state that expresses or retains the capacity to re-express a combination of lineage-defining transcription factors will have a stable or more flexible gene expression profile. Studies examining the developmental T-box transcription factor T-bet demonstrate the powerful information that is gained from combining in vivo analysis with basic biochemical and molecular mechanism approaches. Significantly, T-bet's ability to physically recruit epigenetic modifying complexes, in particular a Jmjd3 H3K27-demethylase and a Set7/9 H3K4-methyltransferase complex, to its target genes allows T-bet to effectively reverse and establish new epigenetic states. This observation suggests that until T-bet is permanently extinguished, helper T cells will retain some plasticity towards a T-helper 1-like program. Therefore...

‣ A Novel “Four-component” Two-component Signal Transduction Mechanism Regulates Developmental Progression in Myxococcus xanthus*

Jagadeesan, Sakthimala; Mann, Petra; Schink, Christian W.; Higgs, Penelope I.
Fonte: American Society for Biochemistry and Molecular Biology Publicador: American Society for Biochemistry and Molecular Biology
Tipo: Artigo de Revista Científica
Português
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476.71586%
Histidine-aspartate phosphorelays are employed by two-component signal transduction family proteins to mediate responses to specific signals or stimuli in microorganisms and plants. The RedCDEF proteins constitute a novel signaling system in which four two-component proteins comprising a histidine kinase, a histidine-kinase like protein, and two response regulators function together to regulate progression through the elaborate developmental program of Myxococcus xanthus. A combination of in vivo phenotypic analyses of in-frame deletions and non-functional point mutations in each gene as well as in vitro autophosphorylation and phosphotransfer analyses of recombinant proteins indicate that the RedC histidine kinase protein autophosphorylates and donates a phosphoryl group to the single domain response regulator, RedF, to repress progression through the developmental program. To relieve this developmental repression, RedC instead phosphorylates RedD, a dual receiver response regulator protein. Surprisingly, RedD transfers the phosphoryl group to the histidine kinase-like protein RedE, which itself appears to be incapable of autophosphorylation. Phosphorylation of RedE may render RedE accessible to RedF, where it removes the phosphoryl group from RedF-P...

‣ Computational modeling to elucidate molecular mechanisms of epigenetic memory

Xing, Jianhua; Yu, Jin; Zhang, Hang; Tian, Xiao-Jun
Fonte: Universidade Cornell Publicador: Universidade Cornell
Tipo: Artigo de Revista Científica
Publicado em 13/04/2015 Português
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568.34492%
How do mammalian cells that share the same genome exist in notably distinct phenotypes, exhibiting differences in morphology, gene expression patterns, and epigenetic chromatin statuses? Furthermore how do cells of different phenotypes differentiate reproducibly from a single fertilized egg? These are fundamental problems in developmental biology. Epigenetic histone modifications play an important role in the maintenance of different cell phenotypes. The exact molecular mechanism for inheritance of the modification patterns over cell generations remains elusive. The complexity comes partly from the number of molecular species and the broad time scales involved. In recent years mathematical modeling has made significant contributions on elucidating the molecular mechanisms of DNA methylation and histone covalent modification inheritance. We will pedagogically introduce the typical procedure and some technical details of performing a mathematical modeling study, and discuss future developments.; Comment: 36 pages, 4 figures, 2 tables, book chapter

‣ Molecular mechanisms that control mouse and human TCR-αβ and TCR-γδ T cell development

Taghon, Tom; Rothenberg, Ellen V.
Fonte: Springer Publicador: Springer
Tipo: Article; PeerReviewed Formato: application/pdf
Publicado em /12/2008 Português
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477.78805%
Following specification of hematopoietic precursor cells into the T cell lineage, several developmental options remain available to the immature thymocytes. The paradigm is that the outcome of the T cell receptor rearrangements and the corresponding T cell receptor signaling events will be predominant to determine the first of these choices: the αβ versus γδ T cell pathways. Here, we review the thymus-derived environmental signals, the transcriptional mediators, and other molecular mechanisms that are also involved in this decision in both the mouse and human. We discuss the differences in cellular events between the αβ and γδ developmental pathways and try to correlate these with a corresponding complexity of the molecular mechanisms that support them.

‣ Molecular Mechanisms of Notochord Vacuole Formation and Their Role in Zebrafish Development

Ellis, Kathryn Leigh
Fonte: Universidade Duke Publicador: Universidade Duke
Tipo: Dissertação
Publicado em //2014 Português
Relevância na Pesquisa
563.30242%

The notochord plays critical structural and signaling roles during vertebrate development. At the center of the vertebrate notochord is a large fluid-filled organelle, the notochord vacuole. While these highly conserved intracellular structures have been described for decades, little is known about the molecular mechanisms involved in their biogenesis and maintenance. Here we show that zebrafish notochord vacuoles are specialized lysosome-related organelles whose formation and maintenance requires late endosomal trafficking regulated by the vacuole-specific Rab32a, and H+-ATPase-dependent acidification. We establish that notochord vacuoles are required for body axis elongation during embryonic development and identify a novel role for notochord vacuoles in spine morphogenesis. Thus, the vertebrate notochord plays important structural roles beyond early development.

; Dissertation

‣ Molecular Mechanisms of Polycyclic Aromatic Hydrocarbon-induced Teratogenesis in Zebrafish (Danio rerio)

Van Tiem, Lindsey Anne
Fonte: Universidade Duke Publicador: Universidade Duke
Tipo: Dissertação
Publicado em //2011 Português
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475.30684%

Polycyclic aromatic hydrocarbons (PAHs) are ubiquitous environmental contaminants formed from the incomplete combustion of fossil fuels and are found in the environment as complex mixtures. PAHs are developmentally toxic to fish, causing yolk sac edema, hemorrhaging, craniofacial malformations and cardiac defects including impaired heart looping, elongated heart, decreased blood flow, and pericardial effusion. Previous research has shown that many of the toxic effects of PAHs are mediated through the aryl hydrocarbon receptor (AHR), which upregulates phase I and II metabolic genes, but the underlying mechanisms of PAH-induced toxicity are not yet known. The primary goal of this dissertation was to better understand the molecular mechanisms by which PAH mixtures cause developmental toxicity in fish. To this end, the zebrafish (Danio rerio) was used as a developmental model. Simple mixtures consisting of a PAH that is an AHR agonist (benzo[a]pyrene or benzo[k]fluoranthene) and a PAH that is a cytochrome P450 1 (CYP1) inhibitor (fluoranthene) were used in these experiments along with the dioxin-like compound 3,3',4,4',5-pentachlorobiphenyl (PCB-126). Morpholino gene knockdown was used to examine the role of specific genes in response to PAHs...

‣ Activation of developmental signaling pathways in hematopoietic stem cell regeneration

Lento, William
Fonte: Universidade Duke Publicador: Universidade Duke
Tipo: Dissertação
Publicado em //2010 Português
Relevância na Pesquisa
474.5752%

The homeostatic hematopoietic stem cell compartment is comprised of quiescent long term self renewing stem cells and cycling short term stem cells with finite renewal potential. To study the molecular mechanisms governing self renewal of hematopoietic cells we must force them to enter the cell cycle and proliferate. One approach to accomplish this goal is to damage the hematopoietic compartment with ionizing radiation or cytotoxic chemotherapy. Such injuries ablate mature blood cells and drive the primitive stem cells into cycle. I have elected to use a simple model of hematopoietic damage and regeneration to study the molecular mechanisms controlling self renewal in hematopoietic stem cells. At the beginning of this project it was unclear whether the signaling pathways which homeostatically control self renewal are utilized during injury repair. In particular, there is very little understanding of the signals required for regeneration after radiation damage. We hypothesized extracellular signal transduction pathways provided by the microenvironment are critical mediators of the stem cell repair process. To address these topics and extend the previous work generated in our laboratory, I chose to pursue a candidate approach focusing on the Wnt and Notch developmental signaling pathways.

In order to examine the activation and requirement for each signaling cascade after radiation and chemotherapy damage we used a combination of loss of function and reporter mouse models. To this end...