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Marta Llimargas: Mechanisms of morphogenesis and organogenesis

Lab Presentation

Cellular and molecular mechanisms underlying tubular organ morphogenesis

 During development cells organise in time and space in a tightly regulated manner to give rise to functional tissues and organs that match the physiological needs of the organism. Complex genetic networks act in concert to instruct changes at the cellular level that ultimately shape the organs. Interestingly, a few genetic networks are employed in a reiterative manner to control the formation of different organs and tissues, instructing a limited number of cellular mechanisms (e.g. migration, cell rearrangements, cell shape changes, proliferation, among others). The molecular mechanisms by which these genetic networks regulate changes in morphology and behaviour at single cell resolution are diverse and depend on the cellular context, but they are also used reiteratively during morphogenesis. Remarkably, all these genetic, cellular and molecular mechanisms of organ and tissue formation (organogenesis and morphogenesis) have been highly conserved during evolution. Furthermore, these mechanisms not only act during development, but are also required for tissue homeostasis, and when they escape normal regulation, they can lead to different pathologies and malformations. On the other hand, from comparing developmental processes occurring in different organs of different organisms it also emerged that the same mechanisms acting on different contexts can lead to very different outcomes. Therefore, understanding the commonalities and specificities of organogenesis and morphogenesis is an absolute requirement to anticipate organ and tissue development.

Investigating the cellular, molecular and genetic mechanisms in simple model systems is key to understand development, homeostasis and disease. Thanks to the wide scientific background and the technical tools available, Drosophila melanogaster is one of the best-suited models for animal development. We use the formation of epithelial tissues, with a special focus on the analysis of the embryonic tracheal (respiratory) system, to investigate the general mechanisms of organ and tissue formation, and in particular the mechanisms of morphogenesis of branched tubular structures (tubulogenesis). We ask how the common and essential cellular mechanisms of morphogenesis are genetically controlled, and how the genetically controlled changes in morphology and behaviour at single cell resolution contribute to tissue and organ formation.

 

The current projects on-going in the lab focus on:

Research Lines

Interactions tissue/environment during organogenesis.
The tracheal system is surrounded by different extracellular matrices. We investigate their organisation and contribution to tracheal formation. We are particularly interested in the apical extracellular matrix (aECM) secreted by the tracheal cells, with key roles in morphogenesis and physiology. We investigate the synthesis, deposition and turnover of the aECM in the trachea, and the molecular mechanisms by which this aECM controls tracheal morphogenesis at the cellular level.
Contribution and remodelling of Adherens Junctions and cell polarity in epithelial morphogenesis.
Epithelial tissues, like the tracheal tissue, are composed of tightly packed cells that form a continuous sheet. Specialised junctions and protein complexes localised at the plasma membrane (i.e. Adherens Junctions, SubApical Region and Septate Junctions) ensure the essential functions of epithelial tissues providing cell adhesion, apicobasal polarity and a paracellular barrier. During organ formation these epithelial junctions need to be remodelled to allow sufficient flexibility for cell rearrangements, but at the same time they need to be preserved to ensure their functions. On the other hand, in spite of the general roles assigned to these junctions, it is known that they can also be instructive in morphogenesis, regulating specific aspects of tissue formation. In this frame, we investigate how epithelial junctions are remodelled during tracheal formation and how these epithelial structures contribute to specific tracheal morphogenetic events.
Naive and unbiased analysis of tracheal morphogenesis
We previously we carried out in the lab two different genetic screens designed to identify new factors involved in tracheal formation. Based on different criteria like the molecular nature, phenotype or pattern of expression, we have been studying different interesting candidates that informed us of different mechanisms of tracheal formation. We continue this type of analysis as an efficient, productive and unbiased way to approach tracheal development
Marta Llimargas Casanova
  • Marta Llimargas Casanova
  • IBMB-CSIC
  • Baldiri Reixac, 10-12
  • 08028 Barcelona, Spain
  • Phone: +34 93 4037066 / +34 93 4034979
  • E-mail: mlcbmc@ibmb.csic.es

Principal Investigator



Past students

  • Pilar Okenve

    PhD Student

  • Ivette Olivares

    PhD Student

  • Guillem Parés

    PhD Student

  • Barbara Rotstein

    PhD Student

 

  • Letizia A, He D, Astigarraga S, Colombelli J, Hatini V, Llimargas M, Treisman JE. (2019)  Sidekick Is a Key Component of Tricellular Adherens Junctions that Acts to Resolve Cell Rearrangements. Dev Cell. 2019 Aug 5;50(3):313-326.e5. doi: 10.1016/j.devcel.2019.07.007. Epub 2019 Jul 25.

  • Olivares-Castiñeira I, Llimargas M. (2018) Anisotropic Crb accumulation, modulated by Src42A, is coupled to polarised epithelial tube growth in Drosophila.

    PLoS Genet. 2018 Nov 26;14(11):e1007824. doi: 10.1371/journal.pgen.1007824. eCollection 2018 Nov

  • Letizia A, Tosi S, Llimargas M.(2018) Morphogenetic movements affect local tissue organisation during embryonic Drosophila morphogenesis. Eur J Cell Biol. 2018 Mar 15. pii: S0171-9335(17)30311-4. doi: 10.1016/j.ejcb.2018.03.004
  • Olivares-Castiñeira I, Llimargas M. (2017). EGFR controls Drosophila tracheal tube elongation by intracellular trafficking regulation. PLoS Genet. 2017 Jul 5;13(7):e1006882. doi: 10.1371/journal.pgen.1006882
  • Beich-Frandsen, M., Aragón, E., Llimargas, M., Benach, J., Riera, A., Pous, J. & Macias, M.J. (2015). Acta Crystallogr D Biol Crystallogr. 2015 Apr;71(Pt 4):844-53. doi: 10.1107/S1399004715001443
  • Moussian, B., Letizia , A., Martínez-Corrales, G., Rotstein, B., Casali, A., and Llimargas, M. (2015) Deciphering the genetic programme triggering timely and spatially-regulated chitin deposition. PLoS Genet. 2015 Jan 24;11(1):e1004939. doi: 10.1371/journal.pgen.1004939
  • Okenve-Ramos, P. and Llimargas, M. (2014) Fascin, may the Forked be with you. Fly, 8:3, 157-164, DOI:10.4161/fly.34368
  • Okenve-Ramos, P. and Llimargas, M. (2014) A role for fascin in preventing filopodia breakage in Drosophila tracheal cells. Communicative & Integrative Biology, 7:5, 1-4, DOI: 10.4161/cib.29741
  • Okenve-Ramos, P. and Llimargas, M. (2014) Fascin links Btl/FGFR signalling to the actin cytoskeleton during Drosophila tracheal morphogenesis. Development 141 (4): 929-939
  • Letizia, A., Ricardo, S., Moussian, B., Martín, N., and Llimargas, M. (2013). A functional role of the extracellular domain of Crumbs in cell architecture and apicobasal polarity. Journal of Cell Science,126 (10):    2157-2163
  • Letizia, A. and Llimargas,M. (2012). Adherens Junctions and Cadherins in Drosophila Development. in “Adherens junctions: from molecular mechanisms to tissue development and disease”. Subcell Biochem. 2012;60:251-77. Springer
  • Rotstein, B., Molnar D., Adryan, B.* and Llimargas, M.* (2011)(*Authors for correspondence). Tramtrack is genetically upstream of genes controlling tracheal tube size in Drosophila. PLoS One. 2011;6(12):e28985. Epub 2011 Dec 2
  • Letizia, A., Sotillos, S., Campuzano, S. and Llimargas,M. (2011). Regulated Crb accumulation controls apical constriction and invagination in Drosophila tracheal cells.. Journal of Cell Science 124 (2):240-251
  • Llimargas,M. and Casanova, J. (2010). Apical constriction and invagination: a very self-reliant couple. Developmental Biology 344 (1):4-6
  • Shaye DD, Casanova J, Llimargas M (2008). Modulation of intracellular trafficking regulates cell intercalation in the Drosophila trachea. Nat Cell Biol. 10(8):964-70
  • Araújo, S. J., Cela, C and Llimargas,M. (2007). Tramtrack regulates different morphogenetic events during Drosophila tracheal development. Development 134:3665-76
  • Cela, C and Llimargas,M. (2006). Egfr is essential for maintaining epithelial integrity during tracheal remodelling in Drosophila. Development, 133: 3115-25
  • Llimargas, M.*, Strigini, M., Katidou, M., Karagogeos, D. and Casanova, J.* (2004)(*Authors for correspondence). Lachesin is a component of a septate junction based mechanism that controls tube size and epithelial integrity in the Drosophila tracheal system. Development, 131: 181-190.
  • Llimargas, M* and Lawrence, P. A.(2001).(*Author for correspondence). Seven Wnt homologues in Drosophila: A case study of the developing trachea. Proc Natl Acad Sci U S A 98, 14487- 14492
  • Llimargas, M. (2000). Wingless and its signalling pathway have common and separable functions during tracheal development. Development 127, 4407-4417
  • Boube, M., Llimargas, M. and Casanova, J. (2000). Cross-regulatory interactions among tracheal genes support a cooperative model for the induction of tracheal fates in the Drosophila embryo. .Mech Dev. 91, 271-278.
  • Llimargas, M. (1999). The Notch pathway helps to pattern the tips of the Drosophila tracheal branches by selecting cell fates. Development 126, 2355-2364.
  • Llimargas, M.* and Casanova, J. (1999).(*Author for correspondence). EGF signalling regulates cell invagination as well as cell migration during formation of tracheal system in Drosophila. Development Genes and Evolution 209, 174-179.  
  • Llimargas, M. and Casanova, J. (1997). ventral veinless, a POU domain transcription factor, regulates different transduction pathways required for tracheal branching in Drosophila. Development 124, 3273- 328
  • Celis, J.F*., Llimargas, M.*, and Casanova, J. (1995).(* The two authors contributed equally to the work). Ventral veinless, the gene encoding the Cf1a transcription factor, links positional information and cell differentation during embryonic and imaginal development in Drosophila melanogaster. Development 121, 3405- 3416
ONGOING RESEARCH GRANTS

 

PGC2018-098449-B-100
Project: "Mecanismos celulares y moleculares que rigen la morfogénesis de órganos tubulares".
  • Funding Agency: Ministerio de Ciencia, Innovación y Universidades.
  • 2019-2021
  • PI: Marta Llimargas Casanova
BFU2015-68098-P
Project: "Generando tejidos y órganos durante el desarollo de Drosophila melanogaster ".
  • Funding Agency: Ministerio de Economía y Competitividad.
  • 2016-2018
  • PI: Marta Llimargas Casanova
BFU2012-39509-C02-01
Proyecto coordinado: "Mecanismos celulares necesarios para la formación de órganos durante el desarrollo embrionario de Drosophila.". Subproyecto "Análisis de los mecanismos de morfogénesis epitelial durante el desarrollo embrionario de Drosophila melanogaster ".
  • Funding Agency: Ministerio de Economía y Competitividad.
  • 2013-2016
  • PI: Marta Llimargas Casanova
     
BFU2009-09041/BMC
Project: Title: Estudio de los mecanismos de morfogénesis del sistema traqueal de Drosophila melanogaster.
  • Funding Agency: Ministerio de Ciencia e Innovación.
  • 01/01/2010-30/04/2013
  • PI Marta Llimargas Casanova
     
2009 SGR-1333
Mecanismes de tubulogènesi.
  • Funding Agency: AGAUR.
  • 01/08/2019-31/12/2013
  • PI: Marta Llimargas Casanova
     
CSD2007-00008
“From Genes to Shape: analysis of morphogenesis in Drosophila and vertebrates.” Subproyecto “Cellular properties and morphogenesis”
  • Funding Agency: Ministerio de Educación y Ciencia.
  • 10/2007-9/12/2013
  • PI: Dr. G. Morata. Dr. J. Casanova Roca

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