Regulation of tissue growth: a molecular bridge between extrinsic and intrinsic mechanisms = Regulación del crecimiento tisular : un puente molecular entre los mecanismos extrínsecos e intrínsecos

• Autores: Ana Patricia Almeida Ferreira
• Directores de la Tesis: Florenci Serras Rigalt (dir. tes.), Marco Milán Kalbfleisch (dir. tes.)
• Lectura: En la Universitat de Barcelona ( España ) en 2016
• Idioma: inglés
• Tribunal Calificador de la Tesis: Luis Fernando Casares Fernández (presid.), Francesc Cebrià Sánchez (secret.), Hugo Stocker (voc.)
• Programa de doctorado: Programa Oficial de Doctorado en Genética
• Materias:
  • Ciencias de la vida
    • Biología animal (zoología)
      • Desarrollo animal
      • Crecimiento animal
    • Genética
    • Biología de insectos (entomología)
      • Desarrollo de los insectos
• Enlaces
  • Tesis en acceso abierto en: Dipòsit Digital de la UB
• Resumen

  • The final size of a developing organ has to be finely modulated in order to give rise to fully functional organs and organisms. Final size is regulated by nutritional status of the feeding animal through the activity of nutrient sensing pathways, such as Insulin and TOR signaling pathways. In addition, intrinsic signals operate in an autonomous way to control growth and also shape of an organ. How cells integrate distinct inputs (extrinsic and intrinsic signals) to generate organs of appropriate size and shape remains largely unknown. The phosphatidylinositol 3-kinase (PI3K)–phosphatase with tensin homology (PTEN) and tuberous sclerosis complex (TSC)–target of rapamycin (TOR) pathways are frequently activated in human cancer, and this activation is often causative of tumorigenesis. One interesting and yet poorly understood issue is how cells depleted of tumor suppressor genes outcompete neighboring wild type cells, especially during early stages of tumorigenesis after initial mutagenesis and transformation. We utilized the Gal4-UAS system in Drosophila imaginal primordia, highly proliferative and growing tissues, to analyze the impact of restricted activation of these pathways on neighboring wild type cell populations. The results presented in this thesis show that activation of these pathways leads to an expected autonomous induction of tissue overgrowth and to a remarkable nonautonomous reduction in growth and proliferation rates of adjacent cell populations. We show that this nonautonomous response occurs independently of where these pathways are activated, is functional all throughout development, takes place across compartments, is independent of apoptosis and as such distinct from cell competition and is not influenced by the nutritional status of the animal. We presented evidence that the observed autonomous and nonautonomous effects on tissue growth rely on the upregulation of the proteoglycan Dally, a major element involved in modulating the spreading, stability, and activity of the growth promoting Decapentaplegic (Dpp)/transforming growth factor ß (TGF-ß) signaling molecule. First, we observed an upregulation in the expression levels of Dally. Second, Dally overexpression phenocopies the autonomous effects on tissue size and more interestingly the nonautonomous effects on tissue size, growth and proliferation rates, and on Dpp availability and signaling. Third, the autonomous and nonautonomous effects on tissue size were fully rescued by Dally depletion. We propose that the nonautonomous reduction in tissue size is a consequence of reduced Dpp signaling, most probably reflecting increased number of Dpp molecules bound to the overgrowing (Dally overexpressing) tissue and a consequent reduction in the number of available Dpp molecules to the neighboring cell population. In this way a reduction in the amount of available Dpp growth factor contributes to the outcompetition of wild type cells by overgrowing cell populations. This is further supported by the fact that increased levels of the Dpp receptor Tkv, that withdraw the Dpp ligand from the extracellular space, also causes a nonautonomous reduction in tissue size. Whereas nutrient-sensing pathways modulate the final size of the adult structure according to nutrient availability to the feeding animal, Dpp plays an organ-intrinsic role in the coordination of growth and patterning. Thus, our results unravel a role of Dally as a molecular bridge between the organ-intrinsic and organ-extrinsic mechanisms that regulate organ size. As such, it contributes to integrate nutrient sensing and organ scaling, the fitting of pattern to size.