2011 Seminars

Special Christmas Seminar December 21 @ noon
Multipotency and fate restriction of retinal stem cells
Dr. Jochen Widdbrodt
University of Heidelberg, Germany

Summary:Stem cells have the capacity to both self-renew and generate post-mitotic cells. Long-term tracking of individual clones in their natural environment constitutes the ultimate way to validate postembryonic stem cells. We identify retinal stem cells (RSCs) using the temporo/spatial organization of the fish retina and follow the complete offspring of a single cell during the postnatal life. RSCs generate two tissues of the adult fish retina, the neural retina (NR) and the retinal-pigmented epithelium (RPE). Despite their common embryonic origin and tight coordination during continuous organ growth, we prove that NR and RPE are maintained by dedicated RSCs that contribute in a fate-restricted manner to either one or the other tissue. We show that in the NR, RSCs are multipotent and generate all neuron types and glia. The clonal origin of these different cell-types from a multi-potent NSC has far- reaching implications for cell type and tissue homeostasis as well as the evolution of the nervous system.
CABD Seminar December 16 @ noon
LincRNAs: novel components of the p53 network
Dr Maite Huarte
Foundation for Applied Medical Investigation, Centre for Applied Medical Research, CIMA, Universidad de Navarra

Summary:How do cells coordinate and integrate information to produce the adequate gene expression output? For decades genetics has focused in the study of protein-coding genes that control this critical balance. However, cellular networks are fine-tuned and maintained by the coordinated function of not only proteins, but also non-coding RNAs (ncRNAs). In addition to the well-characterized protein coding and microRNAs constituents, large non-coding RNAs are also emerging as important regulatory molecules in tumor-suppressor and oncogenic pathways. Supporting this idea, we have found that the transcription factor p53, which is crucial for the maintenance of cellular homeostasis, specifically regulates the expression of dozens of large intergenic non-coding RNA genes (lincRNAs). These lincRNAs are bona-fide transcriptional targets of p53, and are induced by p53 to modulate specific facets of the p53 cellular response, including the regulation of gene expression through epigenetic mechanisms. Altogether, our work suggests that large non-coding RNAs constitute an unknown layer of regulation of the p53 cellular response that could represent future novel targets for cancer treatments.
CABD Seminar December 2 @ 11am
Patterns of gene expression in development and evolution
Dr Pavel Tomancak
Max Planck Institute of Molecular Cell Biology and Genetics, Dresden, Germany

Summary:I will discuss the various molecular, imaging and image analysis technologies that we developed to monitor patterns of gene expression in development with the highest available resolution in both space and time. Additionally I will discuss our comparative genomics project aiming at explaining the apparent constraint on the evolution of animal morphology during embryogenesis known as the hourglass model.
CABD Seminar November 25 @ noon
Cell-sorting at the A/P-compartment boundary in the Drosophila wing primordium: a computational model to consolidate observed non-local effects of Hedgehog signaling
Dr. Sabine Schilling
Institute of Molecular Systems Biology ETH Zurich, Switzerland

Summary:Adjacent, non-intermingling populations of cells define compartment boundaries; such boundaries are often essential for the positioning and the maintenance of tissue-organizers during growth. In the developing wing primordium of Drosophila melanogaster, signaling by the secreted protein Hedgehog (Hh) is required for compartment boundary maintenance. However, the precise mechanism of Hh input remains poorly understood. Here, we combine experimental observations of perturbed Hh signaling with computer simulations of cellular behavior, and connect physical properties of cells to their Hh signaling status. We find that experimental disruption of Hh signaling has observable effects on cell sorting surprisingly far from the compartment boundary: Patches of cells deficient for Hedgehog signaling transduction form ectopic boundaries to neighboring wild type tissue up to 20 micrometers away from the compartment boundary, which is in contrast to a previous model that confines Hh influence to the compartment boundary itself. We have recapitulated our experimental observations by simulations of Hh production, diffusion and local sensing coupled to mechanical tension along cell-to-cell contact surfaces. Intriguingly, the best results were obtained under the assumption that Hh signaling cannot alter the overall tension force of the cell, but will merely re-distribute it locally inside the cell, relative to the signaling status of neighboring cells. Our results suggest a scenario in which homotypic interactions of a putative Hh target molecule at the cell surface are converted into a mechanical force. Such a scenario could explain why the mechanical output of Hh signaling appears to be confined to the compartment boundary, despite the longer range of the Hh molecule itself. Our study is the first to couple a cellular vertex model describing mechanical properties of cells in a growing tissue, to an explicit model of an entire signaling pathway, including a freely diffusible component.
CABD Seminar November 11 @ noon
Epidermal Stem Cell Behaviors and ECM Dynamics in C. elegans Molting Cycles
Dr Alison Frand
Department of Biological Chemistry David Geffen School of Medicine University of California, Los Angeles

Summary:Unwarranted cell proliferation and pathological remodeling of extracellular matrices (ECM) promote the formation and metastasis of carcinomas. The dynamic interactions among cells and matrices underlying these events can be difficult to study in cell culture and mammalian models. However, related processes occur naturally during molting cycles of the model nematode C. elegans. In this context, epidermal blast cells repeatedly switch between proliferative and quiescent states in phase with four periodic molts, which involve the production and removal of collagen-rich matrices and related cell-ECM attachments. Animals molt at regular ~8 hr intervals, but the anticipated pacemaker had not been defined. Our findings show that LIN‑42, which is the homolog of the human circadian clock gene PERIOD, and conserved nuclear hormone receptors together control the execution of rhythmic molts and progressive development of the epidermis. The enzymatic and signaling cascades essential for productive molts have been identified through full-genome, RNAi-based screens. Further, we have discovered a set of unconventional ECM macromolecules that serve as both structural and instructive components of nematode matrices. Related extracellular fibers are likely assembled and disassembled during every molt. Overall, this talk will describe gene regulatory circuits and downstream factors that coordinate epidermal stem cell behaviors and ECM remodeling during animal development.
CABD Seminar November 4 @ noon
Measuring, Monitoring and Manipulating Morphogenesis with Light
Dr Denise Montell
Department of Biological Chemistry Director, Center for Cell Dynamics Johns Hopkins School of Medicine, Baltimore, USA

Summary:Morphogenetic cell movements are very diverse and many cells travel in groups. We study the similarities and differences between the mechanisms of collective cell migrations and those of single cells. We would also like to understand how cells self-organize into tissues. We use ovarian development in the fruit fly as our major experimental model. Border cell migration serves as a genetically tractable, in vivo model for collective cell migration. We have identified signals that regulate when, where and which cells migrate and invade. Recent studies suggest that E-cadherin plays diverse and central roles both in organizing the cluster as well as in guidance and movement of the cells, in contrast to the general notion that E-cadherin inhibits cell motility. We have also discovered a novel role for Src in cell motility in vivo. On the other hand, using a photo-activatable form of the small GTPase Rac, we have shown that local activation of Rac in one cell can guide the whole cluster in a new direction. This is very similar to the function of Rac in single cells. In addition to promoting protrusion locally, focal Rac activation inhibits protrusion of other cells in the cluster. We are exploring the mechanism by which activation or inactivation of Rac in one cell affects the behavior of other cells in the cluster. Taken together our results support the hypothesis that morphogenetic diversity arises from combinatorial use of modular mechanical properties including cell-cell and cell-matrix adhesion, myosin-mediated contractility, and Rac-mediated protrusion.
CABD Seminar October 28 @ noon
Notch-mediated repression of bantam miRNA contributes to boundary formation in the wing.
Dr. Neus Rafel.

Summary:Subdivision of proliferating tissues into adjacent compartments that do not mix plays a key role in animal development. The Actin cytoskeleton has recently been shown to mediate cell sorting at compartment boundaries, and reduced cell proliferation in boundary cells has been proposed as a way of stabilizing compartment boundaries. Cell interactions mediated by the receptor Notch have been implicated in the specification of compartment boundaries in vertebrates and in Drosophila, but the molecular effectors remain largely unidentified. I will present evidence that Notch mediates boundary formation in the Drosophila wing in part through repression of bantam miRNA. bantam induces cell proliferation and we have identified the Actin regulator Enabled as a new target of bantam. Increased levels of Enabled and reduced proliferation rates contribute to the maintenance of the dorsal-ventral affinity boundary. The activity of Notch also defines, through the homeobox-containing gene cut, a distinct population of boundary cells at the dorsal-ventral (DV) interface that helps to segregate boundary from non-boundary cells and contributes to the maintenance of the DV affinity boundary.
CABD Seminar October 21 @ noon
The role of genes and the environment in humans longevity.
Nir Barzilai MD
Einstein's Nathan Shock Center of excellence in the biology of aging Albert Einstein College of Medicine NY, USA

Summary:Despite evidence for a substantial genetic component, the inherited biological factors that promote extended life span (longevity) in humans remain unknown. We assessed phenotype and genotype of over 540 subjects with exceptional longevity (centenarians) and their families. The families of the longest living subjects are very distinct by their lipid profile (High HDL levels and large lipoprotein particle sizes). However no major role of lifestyle factor was noted in these subjects as the rates of overweight, smoking, physical activity where generally worse over that reported in their cohort. On the other hand, there are several genotypes that have been significant in such subjects, including those in the GH/IGF pathway, lipid metabolism, thyroid metabolism, and FOXO3A that have been confirmed in other groups. These findings indicate that the genome of subjects with exceptional longevity is significantly different than those who die at a younger age, and that this genome has been protecting them against some of the worst environmental factors.
CABD Seminar October 14 @ 11am
Nanocomposites materials for target delivery and sensing.
Dr Pilar Rivera Gil
Biophotonics, Department of Physics, Philipps University Marburg, Germany
CABD Seminar October 7 @ noon
Opposing effects of Prohibitin on C. elegans ageing: understanding mitochondrial signalling crosstalk.
Dr. Marta Artal-Sanz
Laboratory for Bioinformatics and Molecular Genetics, Albert-Ludwigs-University of Freiburg, Germany

Summary:Mitochondrial biogenesis and function are primary longevity determinants in eukaryotes. However, the molecular mechanisms regulating mitochondrial energy metabolism during ageing are poorly understood. Prohibitins (PHB) are ubiquitous and evolutionarily conserved proteins, which form a ring-like, high molecular weight complex at the inner membrane of mitochondria. Prohibitin function has been implicated in carcinogenesis and replicative senescence. In the nematode C. elegans, prohibitin deficiency shortens the lifespan of otherwise wild type animals. However, remarkably, knockdown of prohibitin promotes longevity in insulin and TGF-β mutants or under dietary restriction. In addition, prohibitin deficiency extends the lifespan of animals with compromised mitochondrial function or fat metabolism and restores normal lifespan in mutants with lethal germline tumours. These findings reveal an intricate mechanism of regulating mitochondrial energy metabolism and fat utilization depending on intrinsic and extrinsic cues. The striking opposite effect of prohibitin on longevity under different conditions offers a unique opportunity to understand how mitochondrial function relates with the cellular signalling status to regulate longevity. We aim at identifying the molecular signalling pathways involved in the cellular response to PHB depletion under normal and reduced insulin signalling conditions.
CABD Seminar July 19 @ noon

Dr. Vincent Galy
Biologie du Développement, Université Pierre et Marie Curie
CABD Seminar July 15 @ noon
Sensory mechanisms that influence physiology and aging
Dr. Joy Alcedo
Friedrich Miescher Institute for Biomedical Research, Basel Switzerland

Summary:For optimal survival, animals sense and translate complex environmental cues into appropriate behavioral and physiological responses. Consistent with this idea, the C. elegans and D. melanogaster sensory systems have been shown to influence lifespan through signaling pathways, like the insulin/IGF-1 pathway, that control physiology. Since the sensory system perceives many different environmental cues, which could elicit different physiological outcomes, it is likely that sensory neurons will affect lifespan through several mechanisms. Indeed, sensory neurons express different neuropeptides that could regulate many physiological processes in response to distinct sensory cues, although the precise mechanisms through which these cues regulate neuropeptide signaling and influence physiology remain unknown. Recently, we have found that the sensory influence on C. elegans lifespan is mediated by a neuropeptide neuromedin U signaling pathway through food-type recognition, which is a mechanism distinct from food-level restriction. We have also shown that this neuromedin U pathway regulates C. elegans lifespan in parallel to its food type-dependent regulation of development and reproduction. In contrast, we have found that other neuropeptides, i.e., three members of the large C. elegans insulin-like peptide (ILP) family that are expressed in different subsets of sensory neurons, have little or no effect on lifespan. However, these ILPs encode sensory information to regulate developmental plasticity, which raises the possibility that the remaining ILPs encode other environmental information to regulate physiology, including lifespan. Together our studies could provide insight into how the sensory system and neuropeptide signaling pathways act together to regulate different physiological processes in response to the changing quality of the environment.
CABD Seminar July 8 @ noon
NGS (Next Generation Sequencing): Opportunities and challenges.
Eduardo Pareja and Raquel Tobes
Era7 Information Technologies SLU

Summary: _ Next generation sequencing technologies _ Which is the better technology for each problem? _ From experimental design to bioinformatics analysis _ Exome analysis _ Transcriptome analysis: o Gene catalog (normalized cDNA library) o Differential expression analysis (Sequencing vs arrays) _ Bacterial genome annotation: BG7 a new approach for annotation of genomes sequenced with NGS _ Our bioinformatics pipelines for transcriptome and genome analysis _ Bio4j: our system of organizing and managing biological data integrating Uniprot proteins, Refseq genomes and Gene Ontology in a unified network with interlinked components. Advanced querying and retrieval for complex data and functional annotations of genes and proteins. _ Era7 Bioinformatics Services: o Transcriptome analysis o Bacterial genome annotation o Cloud computing (computation and storage) o Bioinformatics support
CABD Seminar July 1 @ noon
Mechanisms determining adult body size and proportions in response to nutrition in Drosophila melanogaster
Dr Christen Mirth
Instituto Gulbenkian de Ciência, Fundação Calouste Gulbenkian, Oeiras, Portugal

Summary: Our lab focuses on understanding how environmental cues, such as nutrition, affect larval growth to produce a correctly sized adult. We use the fruit fly, Drosophila melanogaster, to elucidate the signalling pathways involved in determining final size. Nutrition regulates body size by controlling larval growth rates and the duration of the larval growth period. Nutrition-sensitive signalling, via the insulin and target of rapamycin (TOR) signalling pathways, regulates the rate of growth. Furthermore, insulin and TOR act to control the duration of growth by regulating the production of the steroid moulting hormone ecdysone. Our work both examines the molecules responsible for crosstalk between the insulin, TOR and ecdysone signalling pathways and how these signalling pathways coordinate the growth and patterning of different organ.
CABD Seminar June 3 @ noon
Dissecting the pathways underlying neuronal specification in mammals
Dr Tristán Rodríguez
Imperial College, London, UK
CABD Seminar May 27 @ noon
Mammalian retinal cell differentiation: Our adventures using biology to drive analysis of large data sets
Dr. Heather Greenlee
University of Iowa, USA
CABD Seminar May 26 @ noon
iGEM and Synthetic Biology based in standard parts
Dr. Randy Rettberg
Massachussets Institute of Technology
CABD Seminar May 20 @ noon
Patterning and cell fate specification in the Nervous System: the establishment of rhombomeric boundaries
Dr. Cristina Pujades
DCEXS-UPF, PRBB, Barcelona

Summary: We are mainly interested in how tissues are patterned and cells specified in the Nervous System during embryonic development. Our work focuses on the study of how interhombomericboundaries are formed within the hindbrain, and which are the cellular mechanisms involved. In addition, we will discuss as well the role of hindbrain signals in the development of adjacent structures such as the inner ear, inparticular cell fate specification in the sensory patches.
CABD Seminar-UNIA Masters seminar May 13 @ noon
Is mitochondrial complex I a master regulator of aging process?
Dr. Alberto Sanz.
Mitochondrial Gerontology and Age-Related Diseases Group Institute of Biomedical Technology, University of Tampere (Finland) http://www.uta.fi/imt/finmit/howylab/personnel/alberto.php

Summary: Mitochondria are considered major regulators of longevity, although their exact role in aging is not fully understood. Data from different laboratories show a negative correlation between reactive oxygen species (ROS) generated by complex I and lifespan. This suggests that complex I has a central role in the regulation of longevity. In order to test the importance of complex I during aging, we have ectopically expressed the NADH dehydrogenase internal 1 (NDI1) from Saccharomyces cerevisiae in Drosophila melanogaster. NDI1 is a single polypeptide that oxidizes matrix NADH to NAD+ without proton pumping. Expression of NDI1 increases lifespan and reduces the amount of mitochondrial Reactive Oxygen Species (mtROS) generated at old ages. In addition, it increases the ratio NAD+/NADH and reduces glyco- and lipooxidative damage in vivo. We proposed that complex I is a master regulator of longevity. The control of longevity would be based on a ROS dependent mechanism (production of superoxide at flavin or iron-sulfur clusters) and a ROS independent mechanism (control of the ratio NAD+/NADH). The regulation of the ratio NAD+/NADH would determine the generation of glyco- and lipooxidative damage and the activity of pro-survival enzymes such as sirtuins.
CABD Seminar May 12 @ noon
Development of chromatin state during early vertebrate embryogenesis
Dr. Gert Jan Veenstra.
Radboud University Nijmegen, Department of Molecular Biology, Faculty of Science, Nijmegen Centre for Molecular Life Sciences, Nijmegen, The Netherlands

Summary: The spectacular development of a single cell into a complex, multicellular organism is one of the most fascinating topics in biology. Essential for pluripotency is the cell's state of chromatin, how genes are marked for activation or repression by epigenetic mechanisms. Little is known, however, about the developmental origins of chromatin state and its regulation. We have generated chromatin state maps of embryos of the tetrapod Xenopus tropicalis using deep sequencing (ChIP-seq). The appearance of histone H3 lysine 4 methylation (H3K4me3) coincides with zygotic gene activation, whereas H3K27me3 is predominantly deposited subsequently, revealing a hierarchy in the spatial control of zygotic gene activation (Akkers et al., 2009, Developmental Cell). To further analyze this phenomenon we have assessed its dynamics in early development, including pluripotent blastula stages in which germ layer induction has not yet taken place. The results show that embryonic chromatin dynamics is characterized by three distinct events: (1) Promoter marking by H3K4me3 at blastula stages in the absence of significant H3K27me3, (2) Local nucleation of H3K27me3 at specific loci, (3) spreading of H3K27me3 from these initial nucleation sites into broader domains of facultative heterochromatin during gastrulation. In addition, we have profiled DNA methylation using methyl-capture-sequencing. DNA methylation is relatively depleted in large H3K27me3 domains, indicating these two repression pathways have different roles. Comparison with chromatin state maps of human ES cells reveals strong conservation of epigenetic makeup and gene regulation between the two systems. Strikingly, genes that are highly expressed in human pluripotent cells and in Xenopus embryos but not in differentiated cells exhibit relatively high methylation in both promoters and gene bodies in embryos. As it turns out, the repressive potential of DNA methylation is limited in early embryos, as methylated promoters are robustly transcribed in blastula and gastrula-stage embryos, but not in oocytes or late embryos where methylated templates are repressed efficiently. The results point to a permissive chromatin state when the embryonic genome is activated at the pluripotent mid-blastula stage; this permissive chromatin state is subsequently constrained by H3K27 methylation coincident with embryonic induction, with a more dominant role for DNA methylation-dependent repression during organogenesis and differentiation.
CABD Seminar May 11 @ noon
Cancer Methylome Profiling using Methyl-DNA Capture
Dr. Arjen Brinkman
NCMLS. Nijmegen

Summary: Comprehensive mapping of DNA methylation in relevant clinical cohorts is likely to identify new cancer-related aberrations that represent potential biomarkers or novel drug targets. We have developed MethylCap-seq, a robust procedure for genome-wide profiling of DNA methylation. The approach consists of the capture of methylated DNA using an MBD protein domain, and subsequent next-generation sequencing of DNA from multiple eluates. The enrichment reached within the individual eluates allows for cost-effective deep sequence coverage. The profiles together yield a detailed genome-wide map of methylated regions and readily allows detection of differential DNA methylation in known and novel regions. Profiles from different cancer-types or cancer-subclasses allow classification based on their whole-genome DNA methylation profiles.
CABD Seminar April 28 @ noon
Architecture of inherited susceptibility to common cancer
Dr. Richard Houlston
CABD Seminar April 8 @ noon
Shift Happens: the Evolutionary and Developmental Dynamics of the Gap Gene Network
Dr. Johannes Jaeger
CRG, Barcelona

Summary: Evolutionary developmental biology tries to close the gap between molecular evolution and phenotypic change. This requires a quantitative systems-level understanding of the gene networks underlying development across multiple levels from the molecular to the organismic. Obtaining such an understanding is challenging due to the large number of factors involved. We depend on computational models for this task. I present a reverse-engineering approach, where gene regulatory interactions are inferred from quantitative expression data, using data-driven mathematical models (called gene circuits). Gene circuit models of the gap gene network of Drosophila reproduce observed gene expression with high precision and temporal resolution and reveal a dynamic mechanism for the control of positional information through shifts of gap gene expression domains. We are extending this approach to a comparative study of the gap gene network between different species of dipterans (flies, midges and mosquitoes). I present preliminary results on data quantification and modeling for gap genes in the scuttle fly Megaselia abdita, and the moth midge Clogmia albipunctata. Our approach yields predictions of how changes of gene regulatory feedback affect the timing and positioning of expression domains. These predictions will be tested experimentally using RNA interference in all three species. No such quantitative systems-level analysis of an evolving gene regulatory network has been achieved to date.
CABD Seminar April 1 @ noon
Functional architecture of the nucleus
Dr. Boris Joffe
Epigenetics, Dept Biology II, University of Munich (LMU), Germany D-82152

Summary: The linear sequence of the human genome would be more than 2 meters long if stretched at the compaction level normal for chromatin. However, when functionally active, chromatin is packed in the nuclei down to 5-6 µm in diameter. To assure the functionality, the arrangement of chromatin in the nuclear space should be highly ordered. What is important for this order and how this order is established after mitosis and during terminal differentiation are cardinal questions for nuclear biology. Chromatin arrangement can be considered in two frames of reference, the global nuclear one and the chromosomal one. In other words, one can analyze how chromatin regions with different functional properties are positioned in the nucleus and how this 3-dimentional pizza is cut to pieces / chromosomes. Recently, a 2-tired scheme of global chromosome arrangement started to establish itself (Solovei et al 2009; Naumova and Dekker 2010, Joffe et al 2010). It suggests that (i) heterochromatin is collected in two compartments, perinuclear (along the nuclear border) and perinucleolar (along the margins of the nucleoli) and (ii) that chromatin thread weaves in such a way that euchromatic chromatin regions loop from these two compartments towards one another, forming an euchromatin compartment between the two heterochromatic subcompartments. The functional aspect of this model suggests that euchromatic zone also contains high concentration of transcription and splicing, so that the two-tires organization facilitates separation of transcriptionally active and silent nuclear domains. In human, smaller chromosomes are also gene-richer ones. Larger, gene-poorer chromosomes tend to occupy more peripheral positions than the smaller gene-richer ones. Thus, the larger chromosomes appear to be preferably associated with the perinuclear tire, the smaller ones with the perinucleolar tire. Arrangement of chromosomes during mitosis seems to play an important role in the establishment of this spatial arrangement.
CABD Seminar April 1 @ 11am
Large scale chromatin folding in mature and differentiating inverted nuclei of mouse rod photoreceptor cells
Dr. Irina Solovei
Epigenetics, Dept Biology II, University of Munich (LMU), Germany D-82152

Summary: The majority of the eukaryotic nuclei have conventional nuclear architecture which means that heterochromatin lines nuclear envelope and the nucleoli, whereas euchromatin occupies the space between the two heterochromatic domains. In mouse rod photoreceptor cells this pattern is inverted: subcentromeric satellite DNA (C-bands of mitotic chromosomes) forms a core of the nucleus surrounded by a thick shell of LINE enriched heterochromatin (G-bands), SINE enriched euchromatin (R-bands) forms the outermost shell. The inverted nuclear architecture occurs only in rods of nocturnal mammals. It transforms their nuclei to microlenses which reduce photon losses and thus improve nocturnal vision (Solovei et al. 2009). Due to symmetric concentric organization and clear separation of the main chromatin classes, inverted nuclei of mouse rod photoreceptors suggest a unique model to study the role that the spatial organization of chromatin plays in nuclear functions and establishment of specific nuclear architecture during differentiation. The inverted pattern is formed by remodeling of the conventional one during the terminal differentiation of the rod cells which takes several weeks. During rod differentiation (1) the chromocenters, initially adjoining the nuclear border, fuse to a single central chromocenter and (2) LINE-rich heterochromatin, initially lining nuclear border, separates from the nuclear envelope and concentrate around fusing chromocenters. LINE-rich heterochromatin decompacts and tends to acquire radial orientation of the chromosome thread, which probably contributes to the optical properties of the inverted nuclei. Surprisingly, intense transcription takes place not only in mature rods but also during all this major nuclear remodeling. This suggests that functional activity of the nucleus demands not certain positions of chromatin in the nucleus, but rather faithful positioning of the chromatin regions in a zone occupied by the same chromatin class.
CABD Seminar March 31 @ noon
Multicellular genes in unicellular lineages or how comparative genomics is modifying our view on metazoan origins
Dr. Iñaki Ruiz-Trillo
Investigador ICREA y profesor asociado al Dept. Genética, UB

Summary: The emergence of multicellular animals or metazoans from their single-celled ancestors is one of the most important evolutionary transitions in the history of life. However, little is known about how this transition took place. Thus, a multi-taxon genome-sequencing initiative, named UNICORN, was launched with the aim to gain insights into metazoan origins. Recent genome data from the UNICORN project has identified a rich genetic repertoire of “multicellular” genes in unicellular relatives of metazoans. For example, the amoeba Capsaspora owczarzaki, a close relative to metazoans, encodes both cadherins and integrins, which are absent in plants and fungi and which were thought to be metazoan-specific. Moreover, the genome of Capsaspora encodes transcription factors that are key to animal development, such as T-box genes or Runx, as well as dozens of protein tyrosine kinases. These findings challenge previous views in which the origin of metazoan multicellularity was thought to be accompanied by the invention and diversification of genes families specifically involved in multicellularity. This opens new questions, such as the role those “multicellular” genes are playing in an unicellular context, and how were they co-adapted into the new (multicellular) functions. Current and future efforts to answer those questions will be discussed.
CABD Seminar March 25 @ noon
Mechanisms of cell coordination in epithelial morphogenesis
Dr. Rodrigo Fernandez-Gonzalez
Postdoctoral Research Fellow Developmental Biology Program Sloan-Kettering Institute 430 E. 67th St, RRL 1029 New York, NY 10065 USA

Summary: Epithelial morphogenesis is driven by contractile actin-myosin networks that generate mechanical force. Elongation of the body axis is a conserved morphogenetic process that occurs through coordinated movements of cell intercalation in the Drosophila embryo. Actin and myosin II localize to two distinct pools in intercalating cells, one associated with the contraction of cell-cell junctions during intercalation and another located at the medial-apical cortex. Using biophysical methods and quantitative imaging we showed that mechanical tension is necessary and sufficient for myosin cortical localization through the selective stabilization of myosin at cell junctions under increased tension. These results demonstrate that myosin both generates and is regulated by tension in a positive feedback loop that is predicted to increase the number of cells engaged in contractile behavior. Simultaneously, we found that intercalating cells undergo anisotropic cell shape fluctuations, with rapid cycles of apical contraction and expansion associated with the assembly and disassembly of highly dynamic, medial actin-myosin structures. We have identified a novel role for medial actin-myosin structures in wound healing during axis elongation. Upon wounding, actin and myosin assemble dense medial meshworks associated with dramatic contraction and closure of the wound. We found that the assembly of medial contractile structures in wound healing is specific to early Drosophila embryos. We are currently investigating the cellular, molecular and mechanical elements that regulate wound healing in early and late embryos to identify the mechanisms of efficient wound closure.
CABD Seminar March 18 @ noon
Logical models provide insights into regulatory networks dynamics
Dr. Claudine Chaouiya
IGC, Oeiras, Portugal

Summary: The control of essential cellular processes (proliferation, differentiation, apoptosis) is driven by a great amount of molecular actors interacting through a variety of regulatory mechanisms. Large and complex interaction networks are thus delineated, calling for dedicated modelling methods to understand (and predict) their behaviours in normal (and perturbed) situations. I will briefly introduce the logical formalism, which provides qualitative yet informative models and is well adapted to cope with the lack of quantitative, detailed data on regulatory mechanisms. Although these models constitute abstractions simplifying the biological reality, we still need to cope with challenging issues due to the complexity of ever increasing networks. In this context, we develop dedicated techniques to handle the analysis of comprehensive models or regulatory networks (discrete simulation, attractor identification, feedback circuit analysis, model reduction, etc.). I will illustrate these methods through the analysis of the logical model of the segment-polarity module involved in Drosophila segmentation (Sanchez et al. Int J Dev Biol. 2008). This model, which encompasses six embryonic cells each with a dozen of regulatory components, recapitulates the main characteristics of wild-type and mutant development.
CABD Seminar March 11 @ noon
Stochasticity in cellular decision making: how cells play dice and like it
Dr. Jordi Garcia-Ojalvo
Universitat Politecnica de Catalunya, Spain

Summary: Recent years have witnessed an increasing amount of studies characterizing randomness in cell behavior. The question now is whether such noise is something that cells have to cope with, or if it is actually something useful (and necessary) for proper cellular function. In this talk I will review some examples of how cells in fact use noise for making decisions, dealing with uncertain environments, and remaining in a primed state that allows them to make decisions quickly and efficiently.
CABD Seminar February 25 @ noon
Morphodynamics or how pattern formation and morphogenesis get coordinated in development and evolution
Dr. Isaac Salazar-Cuidad.
UAB, Barcelona

Summary: Most of the best studied developmental systems (such as Drosophila segmentation and imginal disc early patterning) exhibit modest amounts of cell movement. There is compeling evidence that in many other systems there is extensive cell movement co-occuring with cell signalling. Since the cells receiving and sending signals are changing their positions constantly the whole pattern formation dynamics are difficult to understand (french flag positional information metaphors simply won't work). I will suggest how this co-occuerence, called morphodynamics, has important consequences for our understanding of pattern formation, morphogenesis and evolution. Morphodynamic mechanisms involve a complex relationship between genotype and phenotype and a complex logic that is difficult to dissect from classical genetic analysis. I will introduce specific examples of the morphodynamic systems to suggest how the understanding of morphodynamics requires a conceptual change in how models and experiments in developmental biology are designed. The phylogenetic spread of these types of mechanisms will be reviewed to evaluate the relevance of morphodynamics to understand animal development. Finally I will discuss models that show that morphodynamics is likely to arise and drive the direction of evolutionary change in many contexts in evolution and development. This in turns provides a new step towards the yet unaccomplised integration between developmental and evolutionary biology.
CABD Seminar February 18 @ 10:30am
Puzzling out the Mechanical Stability of the DV Organizer of the Wing Imaginal Disc
Dr. Javier Buceta.
CoSMo lab, PCB, Barcelona

Summary: During the course of development, tissues are subjected to forces that shape the primordia. Within this context we have studied the dynamics and stability of the dorsal-ventral organizer of the wing imaginal disc of Drosophila as cell proliferation advances. Our approach is based on a generalized vertex model to perform in silico experiments that is fully dynamical and takes into account the available experimental data. Thus, in this talk 'll show that our results shed light on the complex interplay between the cytoskeleton mechanics, the cell cycle, the cell growth, and the cellular interactions, in order to shape the dorsal-ventral organizer as a robust source of positional information and a lineage controller. All in all, our results provide novel insights into the developmental mechanisms that drive the dynamics of the DV organizer and set a definition of the so-called Notch fence model in quantitative terms.
CABD Seminar January 28@ noon
Centrosome Biogenesis and Evolution
Dr. Monica Bettencourt Dias
Instituto Gulbenkian de Ciência en Oeiras, Portugal

Summary: Centrosome Biogenesis and Evolution The centriole/basal body (CBB) nucleates cilia and flagella and is an essential component of the centrosome. Centrosomes are the major microtubule organizer in animal cells, and cilia and flagella are important in signaling and motility. Abnormalities in microtubule-organizing structures and in cell polarity have been observed in a variety of human diseases, such as cancer and cystic kidneys. In this talk I will discuss the identification and characterization of key components of the centriole, whose regulation dictates centriole and centrosome numbers and centriole architecture. Misregulation of several of these components leads to abnormal embryonic divisions and sterility in the fruit fly. Given the diversity in cellular contexts encountered in eukaryotes, but remarkable conservation of centriole morphology, we asked whether we could obtain general mechanistic principles that explain centriole assembly. We profiled each component of the human centriole assembly machinery across eukaryotes and found one universal module (UNIMOD) that correlates with the occurrence of centrioles, while others emerged in a taxon-specific manner. We propose that the UNIMOD explains the conservation of centriole architecture and that taxon and tissue-specific molecular innovations play a role in coordinating centriole biogenesis and function to different cellular contexts.
CABD Seminar January 21@ noon
Methods in Quantitative Proteomics
Dr. Laura Tomas
Area Microbiologia, CABD

Summary: The proteome is the entire set of proteins expressed by a genome, cell, tissue or organism. More specifically, it is the set of expressed proteins in a given type of cells or organism at a given time under defined conditions. The proteome depends, not only on gene expression but also by the requirements or stresses, that a cell or organism undergoes, so it differs from cell to cell and from time to time. The term Proteomics is the large-scale study of proteins, particularly their structures and functions. Genomics, or gene expression pattern, not always correlates to proteomics, since mRNA is not always translated into a protein, and the amount of protein produced for a given amount of mRNA depends on the transcribed gene, but also on the physiological status of the cell. Proteomics confirms the presence of a protein and provides a direct measure of the quantity. In the last years, the advances on mass spectrometry has allowed to obtain quantitative information about all proteins in a sample. This is Quantitative Proteomic, a set of techniques that, rather than just providing lists of proteins identified in a certain sample, yields information about differences between samples. We will introduce, in this talk, the latest techniques developed for Quantitative Proteomics, those that need peptide labelling, as DIGE, iTRAQ or SILAC, and a label-free technique, SELDI-TOFF.
CABD Seminar January 18@ noon
Roles of the homeobox genes Six3 and Prox1 during mammalian brain development and neurogenesis
Dr. Alfonso Lavado.
Dept of Genetics, St. Jude Children’s Research Hospital (Memphis, TN, USA) (Laboratory of Guillermo Oliver

Summary: In this talk I am going to discuss several of the roles of Six3 and Prox1 during mammalian brain morphogenesis and neurogenesis. During vertebrate head development, the level of Wnt activity specifies posterior-to-anterior fates within the neural plate. Six3 directly represses Wnt1 in vivo, and Six3-null embryos lack the telencephalon. To better understand how antagonists of caudalizing signals function during early mammalian forebrain development we performed a detailed temporal characterization of the developing Six3-null and Six3;Wnt1 double-null brains. We found that the Six3-null brain is gradually posteriorized. We also conclude that Six3-mediated repression of Wnt1 is required for the formation of the diencephalon, while another Six3 activity is required for the formation of the telencephalon. The homeobox gene Prox1, the gene related to prospero, is expressed in several brain regions during prenatal and postnatal stages of development. However, no data was available on the functional role of Prox1 during brain development. We found that Prox1 is necessary for granule cell neurogenesis and the formation of the dentate gyrus. We also demonstrated that Prox1-expressing intermediate progenitors are required for adult neural stem cell self-maintenance in the subgranular zone; thus, we have identified a previously unknown non-cell autonomous regulatory feedback mechanism that controls adult neurogenesis in this region of the mammalian brain.
CABD Seminar January 14@ noon
Hox control of appendage specialization: lessons from flies and crustaceans.
Dr. Anastasios (Tassos) Pavlopoulos.
Laboratory for Development and Evolution (Akam group) Department of Zoology, University of Cambridge, UK

Summary: Hox genes play a key role in animal development and evolution, but despite many years of study, it has proved surprisingly difficult to explain the biological specificity of these widely conserved developmental regulators. The complexity of the developmental programs that Hox genes control has impeded our understanding of how the Hox transcription factors bring about particular cell and organ morphologies. To address this problem, I have studied Hox controlled appendage morphogenesis using two complementary systems: one based on the emerging crustacean model Parhyale hawaiensis that is best suited for cell biology studies of tissue morphogenesis, and one Drosophila-based that is best suited to study the gene regulatory networks controlling appendage morphogenesis and cell differentiation. In Parhyale, the spatial and temporal modulation of Hox gene expression specifies distinct types of thoracic and gnathal appendages adapted for specialised functions. This has offered the great advantage to study how morphogenetic mechanisms are deployed differentially in growing appendages to produce the observed differences in size, shape and pattern, and how changes in the expression of Hox genes have driven crustacean appendage evolution. In Drosophila, I have focused on the dorsal flight appendages and the homeotic transformation of wings into halteres by the Hox gene Ultrabithorax (Ubx). How is the diversification of these serially homologous appendages regulated by Ubx at the level of the genome over time? Our study shows that Ubx controls haltere development by regulating hundreds of downstream genes that are largely distinct at different stages of development. These targets include regulatory genes that control patterning and growth, as well as terminal differentiation genes that execute a broad repertoire of cell behaviours and metabolic reactions, showing that Ubx acts at multiple levels of genetic hierarchies. Future directions towards understanding the logic of Hox-controlled developmental programs will be discussed.
CABD Seminar January 12@ noon
Cis-ruption of p63-responsive regulatory elements in developmental disorders.
Dr. Huiqing Zhou
Radboud University Nijmegen Medical Centre, Department of Human Genetics

Summary: The transcription factor p63 is a key factor in ectodermal development. Heterozygous mutations in p63 give rise to seven clinical conditions with autosomal dominant inheritance in human. These conditions are characterized by different combinations of split hand-split foot malformation, cleft lip/palate and ectodermal dysplasia (ED). Numerous p63 target genes have been reported; however, their contributions to the phenotypes in the patients carrying a p63 mutation have remained unclear. To understand the regulatory network of p63 relevant to patient phenotypes, we used a disease model, human primary keratinocytes established from patients with p63 mutations. A combination of genome-wide expression profiling and DNA-binding analysis by Chromatin immunoprecipation followed by deep sequencing (ChIP-seq) in primary keratinocytes revealed a subgroup of direct novel target genes relevant to ED syndromes. A number of validated p63 binding sites appear to be directly involved in related genetic disorders (cleft lip/palate and split hand-split foot malformation). These binding sites can be found in promoter regions and introns, but in several instances also at distances up to 500 kb from the predicted target gene. Gene expression controlled by p63 binding sites identified in our study was confirmed functionally in transgene reporter assays in zebrafish and mouse. Our study not only increases the repertoire of p63 target genes but also provides a concrete molecular basis to elucidate the disease mechanism of p63 and p63-related developmental disorders.
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