Exploring the roles of major signaling pathways in epithelial morphogenesis

• Autores: María Paula Delgado
• Directores de la Tesis: Fernando Martín Belmonte (dir. tes.), Francisco Javier Díez Guerra (tut. tes.)
• Lectura: En la Universidad Autónoma de Madrid ( España ) en 2019
• Idioma: inglés
• Títulos paralelos:
  • Exploración del papel de rutas principales de señalización en la morfogénesis epitelial
• Tribunal Calificador de la Tesis: Elisa Martí Gorostiza (presid.), María Yañez Mo (secret.), Michel Bagnat (voc.), Carlos Estella Sagrado (voc.), Miguel Torres Sánchez (voc.)
• Programa de doctorado: Programa de Doctorado en Biociencias Moleculares por la Universidad Autónoma de Madrid
• Materias:
  • Ciencias de la vida
    • Biología animal (zoología)
      • Desarrollo animal
    • Biología celular
    • Biología molecular
• Enlaces
  • Tesis en acceso abierto en: Biblos-e Archivo
• Resumen

  • One of the central interrogations in developmental biology is how organs acquire their final size and shape. Two main types of cell communication control organ development: biophysical interactions and cell-cell communication through morphogens. Mechanical cues guide different processes, including cell motility, growth and differentiation, and morphogen gradients have critical roles in patterning and organ growth. To which extent are these two different types of communication necessary and what are the concrete molecular players that ensure proper organogenesis are factors that change depending on the organ and the stage of development. In the present thesis, we investigate the potential role of several signaling pathways and mechanical cues from mesenchymal cells during tubulogenesis of different epithelial organs, including the mammary gland and the zebrafish intestine.

    We use the Drosophila wing imaginal disc to understand the mechanism by which Sfrp3 could be modulating the Wnt signaling pathway in mammary gland development, which leads us to the conclusion that SFRP3 is not acting as a negative regulator of Wnt activity, but rather as a diffusor of the Wnt ligands.

    Using Next Generation Sequencing (NGS) techniques, we also report that zebrafish carrying a mutation in the Hedgehog pathway transducer smoothened (smo), which show a previously described defect in single lumen formation in the intestine, also display different gene transcriptional profiles in their intestinal epithelial cells when compared to control fish.

    In addition, we show that the inhibition of TGF-β pathway generates a defect in lumen resolution in the intestine of developing zebrafish embryos as well. Using different zebrafish lines, we try to understand the causes of this phenotype and its possible link with the phenotype observed in the guts of smo mutants. We also detect that mesenchymal cell migration around the epithelial intestinal tube is affected upon TGF-β inhibition, being the lack of physical constraints a potential explanation for the phenotype observed in the case of TGF-β signaling blockade.

    Finally, we also demonstrate that the inhibition of TGF-β alters the epithelial morphogenesis of MDCK spheroids in vitro, and that TGF-β could be regulating the spindle orientation by affecting the machinery that controls this cellular process.