NETWORK
 \  NETWORK
Marian Ros Lasierra (Coordinator)

Instituto de Biomedicina y Biotecnología de Cantabria (CSIC)

The Ros lab studies the molecular basis of morphogenesis: how the formation of a particular form or structure is genetically and molecularly controlled during vertebrate development. The group also pursues to uncover the origins of the developmental defects that lead to human malformations and other diseases. To achieve this task the group combines classical methods of experimental embryology with genetic and biochemical approaches and also more recently with modern genome-wide technologies. The experimental system they use is the developing mouse and chick embryos concentrating mainly, but not exclusively, in the limb. The group has contributed to the identification of the molecular basis of the signaling centers operating in the limb bud including i) the specification of the three proximo-distal segments typical of the tetrapod limb, ii) the formation and function of the apical ectodermal ridge, one major signaling center in the bud, and iii) the control of digit number and identity. Recently, searching to unravel the molecular basis of pentadactyly, the group characterized several murine models with oligo/polydactyly, two common human limb malformations. They found that the removal of Gli3 and 5’Hox genes resulted in severe polydactylous limbs of thin, short, and densely packed digital rays. These phenotypes were concordant with a Turing-type mechanism controlling digit patterning and Hox genes modulating its wavelength. They have also identified the crucial and redundant role played by Sp6 and Sp8, two transcription factors members of the Sp family, in the limb ectoderm. Compound mutations of Sp6 and Sp8 are a model of the Spli Hand/Foot Malformation Syndrome. Finally, by classical grafting experiments in chick embryos and taking advantage of the chicken strain ubiquitously expressing GFP we have shown the intrinsic behavior of the limb progenitor cells in limb proximo-distal patterning.

Publications:

Fernandez-Guerrero M, Yakushiji-Kaminatsui N, Lopez-Delisle L, Zdral S, Darbellay F, Perez-Gomez R, et al. Mammalian-specific ectodermal enhancers control the expression of Hoxc genes in developing nails and hair follicles. Proc Natl Acad Sci. 2020; 117(48):30509–19, https://doi.org/10.1073/pnas.2011078117.

Busby L, Aceituno C, McQueen C, Rich CA, Ros MA*, Towers M.* Sonic hedgehog specifies flight feather positional information in avian wings. Dev. 2020; 147(9):dev188821, https://doi.org/10.1242/DEV.188821.

Bastida MF, Pérez-Gómez R, Trofka A, Zhu J, Rada-Iglesias A, Sheth R, et al. The formation of the thumb requires direct modulation of Gli3 transcription by Hoxa13. Proc Natl Acad Sci. 2020; 117(2):1090–1096, https://doi.org/10.1073/pnas.1919470117.

Pérez-gómez R, Haro E, Fernández-guerrero M, Bastida MF, Ros MA. Role of Hox genes in regulating digit patterning. Int J Dev Biol. 2018; 805:797–805, https://doi.org/10.1387/IJDB.180200MR.

Pickering J, Rich CA, Stainton H, Aceituno C, Chinnaiya K, Saiz-Lopez P, et al. An intrinsic cell cycle timer terminates limb bud outgrowth. Elife. 2018; 7:e37429, https://doi.org/10.7554/eLife.37429.

Saiz-Lopez P, Chinnaiya K, Towers M, Ros MA. Intrinsic properties of limb bud cells can be differentially reset. Development. 2017; 144(3):479–86, https://doi.org/10.1242/dev.137661.

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Miguel Torres Sánchez

Centro Nacional de Investigaciones Cardiovasculares (CNIC)

The Torres group is developing projects towards understanding the cellular basis of early cardiac morphogenesis and its regulation by Transcription Factors of the homeodomain family. The heart is the first organ to acquire its function during embryonic development and has a vital role in pumping nutrients/oxygen. In the early vertebrate embryo, the heart is initially a single primitive contractile cardiac tube. In mammals, it originates from a horseshoe-shaped flat cardiac crescent continuous across the midline that merges at the midline to form a tube. While in recent years significant progress has been made in our understanding of the gene regulatory logic that controls early heart development, approaches toward a comprehensive framework of the cell behaviors underlying the formation of the primitive heart tube from the cardiac crescent are still missing. Cardiac congenital defects are very prevalent (1% of live born) and mostly consist in defects of the complex morphogenetic events involved in cardiac formation. While there is extensive information about the genetic basis of these defects, there is no understanding of the mechanism linking gene function with the morphogenetic events. The group is combining genetic approaches for in vivo labeling of individual cardiac progenitor cells with advanced time-lapse 3D microscopy techniques (2-photon and light sheet microscopy) and embryo culture. Using these approaches, they are obtaining data on the cellular history of the early heart tube and accurate morphometric and dynamic maps of tissue movements and deformations during cardiac tube formation. These data will be used to produce digital descriptions of cardiac tube formation at cellular resolution and generate 4Dmaps of cellular behavior parameters.

Publications:

Díaz-Díaz C Fernández-de-Manuel L, Jiménez-Carretero D, Montoya MC, Clavería C, Torres M (2017). Pluripotency surveillance by Myc-driven competitive elimination of differentiating cells. Developmental Cell, 42: 585–599

Lioux G, Liu, X, Temiño S, Oxendine M, Ayala E, Ortega S, Kelly RG, Oliver G and Torres M (2020). A Second Heart Field-derived vasculogenic niche contributes to cardiac lymphatics. Developmental Cell, 52:350-363. doi: 10.1016/j.devcel.2019.12.006

Delgado I, López-Delgado AC, Roselló-Díez A, Giovinazzo G, Cadenas V, Fernández-de-Manuel L, Sánchez-Cabo F, Anderson MJ, Lewandoski M and Torres M (2020). Proximo-distal positional information encoded by an Fgf-regulated gradient of homeodomain transcription factors in the vertebrate limb. Science Advances, 6(23), EAAZ0742

López-Delgado AC, Delgado I, Cadenas V, Sánchez-Cabo F, and Torres M (2021). Axial skeleton anterior-posterior patterning is regulated through feedback regulation between Meis transcription
factors and retinoic acid. Development, 148: dev193813. doi: 10.1242/dev.193813

Delgado I, Giovinazzo G, Temiño S, Gauthier Y, Balsalobre A, Drouin J and Torres M (2021). Control of mouse limb initiation and antero-posterior patterning by Meis transcription factors. Nature Communications, 12:3086. doi: 10.1038/s41467-021-23373-9

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James Sharpe

Head of EMBL Barcelona
ICREA Research Professor

Title of lab: Multicellular Systems Biology

Our lab aims to further our understanding of organogenesis as a complex system, by bringing together a diverse range of techniques from biology, physics, imaging and computer science. Within this general theme, we focus on two aspects:

(a) We study a well-characterised standard model of development – the vertebrate limb/fin (using the mouse, chick and catshark). We combine experimental data (especially 3D data sets using optical projection tomography) within computational frameworks, to explore and test mechanistic hypotheses about how limb morphogenesis works. Using this approach we are studying both the physical morphogenesis (Boehm et al. 2010, PLoS Biol. and Marcon et al. 2011, PLoS Comp. Biol.) and also the genetic patterning mechanisms (Sheth et al. 2012, Science and Uzkudun et al. 2015 Molecular Systems Biology). We have used this mix of experimental and theoretical work to find evidence supporting the idea that digit patterning is achieved by a Turing reaction-diffusion system (Raspopovic et al. 2014, Science), and also shown that this particular molecular systems has been conserved all the way from fish to mammals (Onimaru et al. 2016, Nature Communications).

(b) In addition to this specific model system, we are also interested in the theoretical principles by which gene regulatory networks can create controlled spatial patterns in multicellular contexts, both in a purely theoretical context (Cotterell et al. 2010, Molecular Systems Biology; Jimenez et al. 2017, Molecular Systems Biology; Diego et al. 2018, Physical Review X), and also in its application to synthetic biology (Schaerli et al. 2014, Nature Communications), and somite patterning (Cotterell et al. 2015, Cell Systems).

Publications:

Cotterell J, Vila-Cejudo M, Batlle-Morera L, Sharpe J. (2020) Endogenous CRISPR/Cas9 arrays for scalable whole-organism lineage tracing. Development 147(9). DOI: 10.1242/dev.184481.

Sharpe J. (2019) Wolpert’s French Flag: what’s the problem? Development 146(24). DOI: 10.1242/dev.185967.

Germann P, Marin-Riera M, Sharpe J. (2019) ya||a: GPU-Powered Spheroid Models for Mesenchyme and Epithelium. Cell Systems 8(3):261-266.e3. DOI: 10.1016/j.cels.2019.02.007.

Diego X, Marcon L, Muller P, Sharpe J. (2018). Key Features of Turing Systems are Determined Purely by Network Topology. PHYSICAL REVIEW X. doi:10.1103/PhysRevX.8.021071.

Onimaru K, Marcon L, Musy M, Tanaka M, Sharpe J. (2016) The fin-to-limb transition as the re-organization of a Turing pattern. Nature Communications 7:11582. DOI: 10.1038/ncomms11582.

Uzkudun M, Marcon L, Sharpe J. (2015) Data-driven modelling of a gene regulatory network for cell fate decisions in the growing limb bud. Molecular Systems Biology. 11(7):815. DOI: 10.15252/msb.20145882.

Raspopovic J, Marcon L, Russo L, Sharpe J. (2014) Digit patterning is controlled by a Bmp-Sox9-Wnt Turing network modulated by morphogen gradients. Science 345(6196):566-570. DOI: 10.1126/science.1252960.

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Andrés Santos Lleó

Universidad Politécnica de Madrid

The Santos group has a relevant experience on image processing tools for understanding embryo development. The understanding of the processes underlying embryo development from a single cell into a multicellular organism is a long-term goal of Developmental Biology that is recently being feasible thanks to the availability of massive 3D +t complex data acquired with new microscopy technologies. But these large quantities of data require automated or semiautomated image processing methods to be possible. Current developments and challenges in biological image processing include algorithms for microscopy multiview fusion, cell nucleus tracking for lineage reconstruction, cell segmentation, multidimensional image registration and gene expression atlases. These tools are to eventually produce in toto reconstruction of the embryo development combining the cell lineage tree with quantitative gene expression data in its spatiotemporal context. In collaboration with scientists from Institut de Neurobiology Alfred Fessard (CNRS, Gif-sur-Yvette, France) and from École Polytechnique (Palaiseau, France), our group has been working on several of the tools required:
(a) A wavelet multiview image fusion for Light-Sheet Fluorescence Microscopy to combine information from all available views into a single volume with improved overall contrast.
(b) A cell lineage reconstruction workflow for early stages of embryo development with dedicated tracking and segmentation tools.
(c) A digital framework for the construction of gene expression atlases of embryogenesis based on image registration algorithms to combine information from different individuals.

Publications:

Pradillo, J.M., Hernández-Jiménez, M., Fernández-Valle, M.E., Medina, V., Ortuño, J.E., Allan, S.M., Proctor, S.D., Garcia-Segura, J.M., Ledesma-Carbayo, M.J., Santos, A., Moro, M.A., Lizasoain, I. “Influence of metabolic syndrome on post-stroke outcome, angiogenesis and vascular function in old rats determined by dynamic contrast enhanced MRI”. J. Cereb. Blood Flow Metab., 41(7):1692-1706. 2021 (doi: 10.1177/0271678X20976412).

Ortuño, J.E., Vegas-Sánchez-Ferrero, G., Gómez-Valverde, J.J., Chen, M.Y., Santos, A., McVeigh, E.R., Ledesma-Carbayo, M.J. “Automatic estimation of aortic and mitral valve displacements in dynamic CTA with 4D graph-cuts”. Med. Image Anal., 65:101748. 2020 (doi: 10.1016/j.media.2020.101748).

Bermejo-Peláez, D., Ash, S.Y., Washko, G.R., San José Estépar, R., Ledesma-Carbayo, M.J. “Classification of Interstitial Lung Abnormality Patterns with an Ensemble of Deep Convolutional Neural Networks”. Sci Rep, 10:338. 2020 (doi: 10.1038/s41598-019-56989-5).

Pablo-Trinidad, A., Butterworth, I., Ledesma-Carbayo, M.J., Vettenburg, T., Sánchez-Ferro, A., Soenksen, L., Durr, N.J., Muñoz-Barrutia, A., Cerrato, C., Humala, K., Fabra Urdiol, M., Del Rio, C., Valles, B., Chen, Y.-B., Hochberg, E.P., Castro-González, C., Bourquard, A. “Automated detection of neutropenia using noninvasive video microscopy of superficial capillaries”. Am. J. Hematol., 94(8):E219-E222. 2019 (doi: 10.1002/ajh.25516).

Gkontra, P., El-Bouri, W.K., Norton, K.-A., Santos, A., Popel, A.S., Payne, S.J., Arroyo, A.G. “Dynamic Changes in Microvascular Flow Conductivity and Perfusion after Myocardial Infarction Shown by Image-Based Modeling”. J. Am. Heart Assoc., 8:e011058. 2019 (doi: 10.1161/JAHA.118.011058).

Gómez-Valverde, J.J., Antón, A., Fatti, G., Liefers, B., Herranz, A., Santos, A., Sánchez, C.I., Ledesma-Carbayo, M.J. “Automatic glaucoma classification using color fundus images based on convolutional neural networks and transfer learning”. Biomed. Opt. Express, 10(2):892-913. 2019 (doi: 10.1364/BOE.10.000892).

Linares, M., Postigo, M., Cuadrado, D., Ortiz-Ruiz, A., Gil-Casanova, S., Vladimirov, A., García-Villena, J., Nuñez-Escobedo, J.M., Martínez-López, J., Rubio, J.M., Ledesma-Carbayo, M.J., Santos, A., Bassat, Q., Luengo-Oroz, M. “Collaborative Intelligence and Gamification for On-Line Malaria Species Differentiation”. Malar. J., 18:21. 2019 (doi: 10.1186/s12936-019-2662-9).

Gkontra, P., Norton, K.-A., Żak, M.M., Clemente, C., Agüero, J., Ibáñez, B., Santos, A., Popel, A.S., Arroyo, A.G. “Deciphering microvascular changes after myocardial infarction through 3D fully automated image analysis”. Sci Rep, 8:1854. 2018 (doi: 10.1038/s41598-018-19758-4).

 

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Jordi Garcia Ojalvo

Universidad Pompeu Fabra

Jordi Garcia-Ojalvo obtained his PhD in statistical physics at the University of Barcelona in 1995. He did postdoctoral work at the Georgia Institute of Technology in Atlanta in 1996, working on laser dynamics, and at the Humboldt University of Berlin in 1998 as an Alexander von Humboldt Fellow, studying noise effects in excitable media. He was IGERT Visiting Professor at Cornell University in Ithaca, New York, in 2003, at which time he began working in the field of systems biology. In 2008 he became Full Professor at the Universitat Politecnica de Catalunya, where he had been teaching applied physics since 1991. He is Visiting Research Associate in Biology at the California Institute of Technology since 2006, and joined the Universitat Pompeu Fabra in October 2012.

Research interest

The laboratory of Dynamical Systems Biology at Universitat Pompeu Fabra is interested in the dynamics of living systems, from unicellular organisms to human beings. We use dynamical phenomena to identify the molecular mechanisms of cellular processes, such as bacterial stress response, spatial self-organization in bacterial biofilms, pluripotency in stem cells, and the immune response to cytokine signaling. Using a combination of theoretical modeling and experimental tools such as time-lapse fluorescence microscopy and microfluidics, we investigate dynamical phenomena including biochemical pulses and oscillations, and study how multiple instances of these processes coexist inside the cell in a coordinated way. At a larger level of organization, we use conductance-based neural models to explain the emergence of collective rhythms in cortical networks. We also work on developing a global description of brain activity by means of mesoscopic neural-mass models, which allows us to link the structural properties of brain networks with their function.

Publications:

Zhu R, Rio-Salgado JM del, Garcia-Ojalvo J, Elowitz MB. Synthetic multistability in mammalian cells. bioRxiv 2021; 2021.02.10.430659. https://doi.org/10.1101/2021.02.10.430659

Torregrosa G, Garcia-Ojalvo J. Mechanistic models of cell-fate transitions from single-cell data. Current Opinion in Systems Biology 2021; 26: 79-86. https://doi.org/10.1016/j.coisb.2021.04.004

Saiz N, Mora-Bitria L, Rahman S, George H, Herder J, Garcia-Ojalvo J, et al. Growth factor-mediated coupling between lineage size and cell fate choice underlies robustness of mammalian development. eLife 2020; 9: e56079. https://doi.org/10.7554/eLife.56079

Matsuda M, Hayashi H, Garcia-Ojalvo J, Yoshioka-Kobayashi K, Kageyama R, Yamanaka Y, et al. Species-specific segmentation clock periods are due to differential biochemical reaction speeds. Science 2020; 369(6510): 1450–5. https://doi.org/10.1126/science.aba7668

Galera-Laporta L, Garcia-Ojalvo J. Antithetic population response to antibiotics in a polybacterial community. Science Advances 2020; 6(10): eaaz5108. https://doi.org/10.1126/sciadv.aaz5108

Martinez-Corral Rosa, Liu Jintao, Prindle Arthur, Süel Gürol M., Garcia-Ojalvo Jordi. Metabolic basis of brain-like electrical signalling in bacterial communities. Philosophical Transactions of the Royal Society B 2019; 374(1774): 20180382. https://doi.org/10.1098/rstb.2018.0382

Martinez-Corral R, Raimundez E, Lin Y, Elowitz MB, Garcia-Ojalvo J. Self-Amplifying Pulsatile Protein Dynamics without Positive Feedback. Cell Systems 2018; 7(4): 453-462.e1. https://doi.org/10.1016/j.cels.2018.08.012

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Marco Milán

Institute for Research in Biomedicine (IRB Barcelona)

Research in Milán lab is centered on the two following topics:

(a) Regulation of tissue size: How the size of a developing organ is regulated by the combined activity of morphogens, growth promoting genes and systemic hormones is probably one of the most interesting questions in developmental biology nowadays. We use the highly proliferative epithelial primordium of the Drosophila wing to address these questions because of its suitability for genetic and molecular manipulations, its well-described developmental biology and its simple epithelial architecture. We take an integrative approach as we aim to understand how the final size of the developing wing is achieved not only during normal development but also in stress conditions. This integrative approach helps to understand the robust interplay between morphogens, growth promoting genes and systemic hormones in normal development or in stress situations, and contributes to identifying emerging stress signaling molecules transiently induced to compensate for tissue loss that can contribute to tumorigenesis in a condition of chronic expression.

(b) Cell and tissue biology of Chromosomal Instability (CIN): CIN, defined as an increased rate of changes in chromosome structure and number, is a feature of most, if not all, solid tumors. While CIN promotes the gain of oncogene-carrying chromosomes and the loss of tumor-suppressor-gene-carrying chromosomes in certain cancers, its impact on the biology of the cell and on the homeostasis of the tissue, as well as its role in tumorigenesis, are far from being fully elucidated. Of note are the highly deleterious effects of CIN as a result of the generation of highly aneuploid karyotypes and the production of DNA damage. Our lab has recently developed an epithelial model of CIN in Drosophila where the relevant cell populations and pertinent cell interactions involved in the response of an epithelial tissue to CIN have been identified and where the molecular mechanisms driving emerging, tumor-like, cellular behaviors have started to be elucidated. Cellular behaviours such as epithelial to mesenchymal (EMT)-like cell fate transition associated with a highly invasive behaviour and the entry into a senescence-like state are currently characterized at the genetic and molecular level.

Publications:

Ferreira A., and Milán M. “Dally proteoglycan mediates the autonomous and non-autonomous effects on tissue growth caused by activation of the PI3K and TOR pathways”. PloS Biology 13(8):e1002239 (2015)

Clemente-Ruiz M., Murillo-Maldonado J.M., Benhra N., Barrio L., Pérez L., Quiroga G., Nebreda A.R., Milán M. “Gene dosage imbalance contributes to chromosomal instability-induced tumorigenesis” Developmental Cell, 36(3):290-302 (2016)

Recasens-Alvarez C., Ferreira A. and Milán M. “JAK/STAT controls organ size and fate specification by regulating morphogen production and Signaling” Nature Communications, 8:13815 (2017)

Barrio L., and Milán M “Boundary Dpp promotes growth of medial and lateral regions of the Drosophila wing” eLife. DOI: 10.7554/eLife.22013 (2017)

Muzzopappa M, Murcia L, and Milán M. “Feedback amplification loop drives malignant growth in epithelial tissues” Proc Natl Acad Sci U S A. 114(35): E7291-E7300 (2017)

Benhra N., Barrio L., Muzzopappa M. and Milán M “Chromosomal instability induces cellular invasion in epithelial tissues” Developmental Cell, 47(2):161-174 (2018)

Barrio L., and Milán M “Regulation of anisotropic tissue growth by two orthogonal signaling centers” Developmental Cell, 52(5):659-672 (2020)

Joy J., Barrio L., Santos-Tapia C., Romão D., Clemente M., and Milán M. “Delineating the pathway that leads to aneuploidy-induced senescence” Developmental Cell, accepted in principle.

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Fernando Casares

CABD (Centro Andaluz de Biología del Desarrollo, CSIC/Universidad Pablo de Olavide/Junta de Andalucía)

The Casares lab investigates the mechanisms that regulate organ size during development an evolution by studying the eyes of insects. Eyes, because they are specialized sensory structures of great biological relevance; and specifically of insects because eyes have undergone an extraordinary morphological and functional diversification within this huge animal group. The lab’s workhorse is the fruitfly Drosophila melanogaster, one of the most powerful model organisms, and uses it as paradigm from which to explore the eyes of close and distant relatives. Exploring the mechanisms of organ growth control is interesting beyond the realm of developmental and evolutionary biology, as they are relevant for understanding the causes of congenital diseases and cancer, as well as for organ engineering. More recently, the lab has initiated a research program on organ regeneration –as a regulated process of organ size and shape control that becomes activated by injury.
Research in the Casares lab uses a variety of approaches, including developmental genetics, genomics, genome editing, quantitative imaging and mathematical modeling.

Publications:

Almudi I, Vizueta J, Wyatt CDR, de Mendoza A, Marlétaz F, Firbas PN, Feuda R, Masiero G, Medina P, Alcaina-Caro A, Cruz F, Gómez-Garrido J, Gut M, Alioto TS, Vargas-Chavez C, Davie K, Misof B, González J, Aerts S, Lister R, Paps J, Rozas J, Sánchez-Gracia A, Irimia M, Maeso I, Casares F. Genomic adaptations to aquatic and aerial life in mayflies and the origin of insect wings. Nat Commun. 2020 May 26;11(1):2631. doi: 10.1038/s41467-020-16284-8.

Casares F, McGregor AP. The evolution and development of eye size in flies. Wiley Interdiscip Rev Dev Biol. 2020 May 12:e380. doi: 10.1002/wdev.380.

Míguez DG, García-Morales D, Casares F. Control of size, fate and time by the Hh morphogen in the eyes of flies. Curr Top Dev Biol. 2020;137:307-332. doi: 10.1016/bs.ctdb.2019.10.011.

Ruiz-Sobrino A, Martín-Blanco CA, Navarro T, Almudí I, Masiero G, Jiménez-Caballero M, Buchwalter DB, Funk DH, Gattolliat JL, Lemos MC, Jiménez F, Casares F. Space colonization by branching trachea explains the morphospace of a simple respiratory organ. Dev Biol. 2020 Jun 1;462(1):50-59. doi: 10.1016/j.ydbio.2020.02.005.

A toggle-switch and a feed-forward loop engage in the control of the Drosophila retinal determination gene network. M Sánchez-Aragón #, J. Cantisán#, C.S. Lopes, C.M Luque, M.C. Lemos*, F. Casares* (2019). Frontiers in Ecology and Evolution, section Evolutionary Developmental Biology. doi.org/10.3389/fevo.2019.00221.

Dynamic Hh signaling can generate temporal information during tissue patterning. D Garcia-Morales, T Navarro, A. Iannini, DG Miguez*, Fernando Casares*. 2019. Development Apr 25;146(8). doi: 10.1242/dev.176933. doi.org/10.1101/451872

Growth and Size Control during Development. Vollmer J, Casares F*, Iber D*. Open Biol. 2017 Nov;7(11). pii: 170190. doi: 10.1098/rsob.170190. Review

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Silvia Muñoz Descalzo

Investigador Doctor de Prestigio ´Viera y Clavijo´, Instituto Universitario de Investigaciones Biomédicas y Sanitarias (IUIBS), Universidad de la Palmas de Gran Canaria (ULPGC)

Our group has three main research topics:

1. Cell Fate Decision:

The key question in Developmental Biology is how cells make decisions in order to generate tissues and organs in a coordinated manner. Every animal starts as a single cell (the fertilized oocyte) which starts dividing, to form different groups of cells: each of these groups will form all the tissues present in the adult but also those required to support embryonic growth. These new emerging cells, how do they know what type of cells do they have to become?, how do they decide on the new cell type to form?

If there is any problem in this cell decision making, the embryo will not grow and result in miscarriage even before the woman acknowledges the pregnancy. It has been calculated that 76% of the miscarriages happens during this stage of embryo development. This decision made by the cells depends on signals that tell them what to do, but also depend on whether the cell is ‘ready’ to acknowledge and interpret these signals: if ready, the cell will form the new cell type instructed by the signal; if not, the cell will do nothing and wait for the next signal that might instruct a different decision.

Often the ‘readiness’ of the cell to respond to the signals depends on where and how much specific protein there is in the cell. Therefore, it is essential to measure where and how much protein each cell has to completely understand how the cell decides on its next behaviour, during normal development or in disease. To measure protein levels we perform quantitative immunofluorescence analysis from confocal images.

In the lab, the decision we are studying to understand how cells make decisions happens just before the mouse embryo implants in the mother’s uterus. At this precise moment, the cells have to decide to change between forming part of the embryo or the tissue that surrounds and supports its growth, the yolk sac. We are using the mouse as a model to understand the processes occurring in the cells and their surroundings (neighbours), while they make decisions about being part of the embryo or yolk sac precursor. The mouse is an ideal model to understand this process as there are clear similarities with humans and important discoveries have been made first in this model system, before undertaking similar studies in humans.

To reduce the number of animals used for experimentation, we also use mouse embryonic stem cells (mESCs) which have been modified to allow the study of this decision. The use of mESCs to understand embryonic development is a new approach which is allowing a rapid progress in the early embryo development field.

We grow these cells as ICM organoids which better resemble the organization, signals and cell behaviour than culturing them as monolayer.

Together with our collaborator Sabine Fischer, we use our quantitative results to investigate how cells coordinate their fate decision based on their neighbours taking into account the three-dimensional distribution of cell within the embryo.

2. Diabetes and Development

Modern lifestyles result in the decrease in birth rate, and increase in obesity and type II diabetes. One factor behind the decrease in birth rates is the increased maternal age. First-time mother’s age has increased up to 30.7 years old in 2017 (eurostat).

High fat diets and sedentary lifestyles are widely spread in modern societies and are responsible for diseases that affect fertility such as obesity and diabetes mellitus (DM). In 2014, 422 million people were diabetic, and its prevalence is increasing alongside the obesity.

Early miscarriage, together with congenital heart and neural tube malformations have been linked to maternal obesity and DM. Moreover, these factors (age, obesity and DM) have an effect in the offspring’s health increasing the susceptibility to develop obesity, DM and cardiovascular diseases.

Both in vivo and in vitro models can aid us in the understanding of the mechanisms behind these complications and, in the long run, towards their prevention and treatment.

Our research focuses on revealing how these different factors affect early embryonic development. Together with Ana Wagner’s research group, we have established new mouse models for DM, obesity and age by modifying their diet at the adolescence and at pre-menopause age. These models allow us to study the preimplantation development and cell fate decisions in the diabetic context.

3. DrosAfrica

Our mission:

http://drosafrica.org/

Publications:

In Vivoand In Vitro Models of Diabetes: A Focus on Pregnancy.  Joaquín Lilao-Garzón, Carmen Valverde-Tercedor, Silvia Muñoz-Descalzo, Yeray Brito-Casillas, Ana M. Wägner. Adv Exp Med Biol. 2020 Jun 6. doi: 10.1007/5584_2020_536.

The transition from local to global patterns governs the differentiation of mouse blastocysts.  Fischer SC, Corujo-Simon E, Lilao-Garzon J, Stelzer EHK, Muñoz-Descalzo S. PLoS One. 2020;15(5):e0233030. doi:10.1371/journal.pone.0233030

Mouse ICM Organoids Reveal Three-Dimensional Cell Fate Clustering. Mathew B, Muñoz-Descalzo S, Corujo-Simon E, Schröter C, Stelzer EHK, Fischer SC. Biophys J. 2019;116(1):127‐141. doi:10.1016/j.bpj.2018.11.011

Wnt/β-catenin signalling and the dynamics of fate decisions in early mouse embryos and embryonic stem (ES) cells.  Muñoz-Descalzo S, Hadjantonakis AK, Arias AM. Semin Cell Dev Biol. 2015;47-48:101‐109. doi:10.1016/j.semcdb.2015.08.011

Oct4 is required for lineage priming in the developing inner cell mass of the mouse blastocyst.  Le Bin, G. C., Muñoz-Descalzo, S., Kurowski, A., Leitch, H., Lou, X., Mansfield, W., Etienne-Dumeau, C., Grabole, N., Mulas, C., Niwa, H., Hadjantonakis, A. K., & Nichols, J. Development. 2014;141(5):1001‐1010. doi:10.1242/dev.096875

A membrane-associated β-catenin/Oct4 complex correlates with ground-state pluripotency in mouse embryonic stem cells. Faunes F; Hayward P; Descalzo SM; Chatterjee SS; Balayo T; Trott J; Christoforou A; Ferrer-Vaquer A; Hadjantonakis AK; Dasgupta R; Arias AM. Development 2013 140: 1171-1183; doi: 10.1242/dev.085654

A competitive protein interaction network buffers Oct4-mediated differentiation to promote pluripotency in embryonic stem cells. Muñoz Descalzo, S., Rué, P., Faunes, F., Hayward, P., Jakt, L. M., Balayo, T., Garcia-Ojalvo, J., & Martinez Arias, A.  Mol Syst Biol. 2013;9:694. Published 2013 Oct 8. doi:10.1038/msb.2013.49

Correlations between the levels of Oct4 and Nanog as a signature for naïve pluripotency in mouse embryonic stem cells.  Muñoz Descalzo S, Rué P, Garcia-Ojalvo J, Martinez Arias A. Stem Cells. 2012;30(12):2683‐2691. doi:10.1002/stem.1230

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Mª José Gómez Benito

Universidad de Zaragoza (M2BE)

The Multiscale in Mechanical and Biological Engineering (M2BE) Research Group from the University from Zaragoza is dedicated to the development of multiscale methodologies and technologies. The aim of the group is to extend these multiscale methodologies to different fields of application of engineering with a special focus on Mechanobiology. We try to understand how cells sense and react to different mechanical environments defined by the extracellular matrix of the different tissues. Understanding these fundamentals could have an important impact to apply it to different technologies in Medicine and Biology, such as regenerative medicine, design of new treatments (mechano-therapies, drug deliver), the design of new materials with new topologies (tissue engineering), prosthesis and implant design, among others.
Our work combines different methodologies (computer simulation models, in-vitro experimentation and clinical validation), which results in the following research lines:
(a) Tissue Engineering and Mechanobiology of bone regeneration, morphogenesis and remodelling.
(b) Mechano-chemical-cellular biology.
(c) Mechanobiology of cancer.
(d) Bacterial Infection Mechanobiology.

Publications:

Bastounis EE, Serrano-Alcalde F, Radhakrishnan P, Engström P, Gómez-Benito MJ, Oswald MS, Yeh YT, Smith JG, Welch MD, García-Aznar JM, Theriot JA. Mechanical competition triggered by innate immune signaling drives the collective extrusion of bacterially infected epithelial cells. Dev Cell. 2021; 56(4):443-460.e11, https://doi.org/10.1016/j.devcel.2021.01.012.

Hervas-Raluy S, Gomez-Benito MJ, Borau-Zamora C, Cóndor M, Garcia-Aznar JM. A new 3D finite element-based approach for computing cell surface tractions assuming nonlinear conditions. PLoS One. 2021; 16(4):e0249018, https://doi.org/10.1371/journal.pone.0249018.

García-Aznar JM, Nasello G, Hervas-Raluy S, Pérez MÁ, Gómez-Benito MJ. Multiscale modeling of bone tissue Mechanobiology. Bone. 2021:116032, https://doi.org/10.1016/j.bone.2021.116032.

Gonçalves IG, Garcia-Aznar JM. Extracellular matrix density regulates the formation of tumour spheroids through cell migration. PLoS Comput Biol. 2021; 17(2):e1008764, https://doi.org/10.1371/journal.pcbi.1008764.

Nieto A, Escribano J, Spill, F, Garcia-Aznar, JM, Gomez-Benito, MJ. Finite element simulation of the structural integrity of endothelial cell monolayers: A step for tumor cell extravasation, Engineering Fracture Mechanics, 2020; 224, https://doi.org/10.1016/j.engfracmech.2019.106718.

Merino-Casallo F, Gomez-Benito MJ, Juste-Lanas Y, Martinez-Cantin R, Garcia-Aznar JM. Integration of in vitro and in silico Models Using Bayesian Optimization With an Application to Stochastic Modeling of Mesenchymal 3D Cell Migration. Front Physiol. 2018; 11; 9:1246, https://doi.org/10.3389/fphys.2018.01246.

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Marta Ibañes Miguez

Universidad de Barcelona

We aim at understanding principles for multicellular organization and patterning in developing organisms. We use theoretical and computational modelling to address mechanisms behind spatiotemporal organization and cell fate choices during animal and plant development. Our research on animals has focused on patterning through Notch signaling, a conserved developmental pathway among Metazoa that mediates interaction between adjacent cells. In plants, we have addressed root growth and cell quiescence as well as vascular patterning, among others, with special attention to Brassinosteroid signaling.

Publications:

Betegón-Putze I, Mercadal J, Bosch N, Planas-Riverola A, Marquès-Bueno M, Vilarrasa-Blasi J, Frigola D, Burkart RC, Martínez C, Conesa A, Sozzani R, Stahl Y, Prat S, Ibañes M, Caño-Delgado AI. “Precise transcriptional control of cellular quiescence by BRAVO/WOX5 complex in Arabidopsis roots.” Mol Syst Biol. 17(6):e9864 (2021).

Sancho JM, Ibañes M.” Landau theory for cellular patterns driven by lateral inhibition interaction. “Phys Rev E. 102(3-1):032404 (2020).

Planas-Riverola A, Gupta A, Betegón-Putze I, Bosch N, Ibañes M, Caño-Delgado AI. “Brassinosteroid signaling in plant development and adaptation to stress “Development 146(5):dev151894. (2019) Review.

Pavelescu I, Vilarrasa-Blasi J, Planas-Riverola A, González-García MP, Caño-Delgado AI, Ibañes M. “A Sizer model for cell differentiation in Arabidopsis thaliana root growth“ Mol Syst Biol. 14(1):e7687 (2018).

Luna-Escalante JC, Formosa-Jordan P, Ibañes M. “Redundancy and cooperation in Notch intercellular signaling” Development 145(1):dev154807 (2018).