In silico modeling of cytoneme-mediated hedgehog signaling in drosophila

Resumen

Morphogenesis is a field inside developmental biology focused in the study of biological, biochemical and biophysical processes that take place to properly develop tissues and organs. To reach shape organization during development requires an accurate spatiotemporal control of several complex processes. Signaling cell-to-cell communication is key to orchestrate all the information required for the control of cell organization. This signaling is achieved in morphogenesis through biochemical molecules, called morphogens. They act at distance in a concentration-dependent manner to regulate the differential activation of target genes. The spatial distribution of a morphogen is called morphogenetic gradient and this is one of the most important concepts in morphogenesis. Even multidisciplinary approaches have been used to analyze and explain how morphogenetic gradients are formed. The transport mechanism since are still under debate, since many morphogenetic signals in metazoans as Delta, EGF, Wnt or Hedgehog (Hh) cannot diffuse freely due to their biochemical properties. A promising mechanism of transport mechanism has been proposed based on direct cell-cell contact dependent on filopodia-like-structures also called cytonemes. In particular, Hh undergoes two lipid modifications that impose Hh to be attached to cell membranes, forcing it to travel loaded in vesicles along cytonemes. Our work was focused on this structures in two drosophila paradigms of Hh signaling by cytonemes: the imaginal wing disc and the abdominal histoblasts nets. The main goal of this thesis has been the multidisciplinary study of the establishment of Hedgehog (Hh) signaling gradient trough cytonemes, and the tight relationship between the cytoneme features and Hh gradient formation. As a conclusion of this work, we developed a detailed in silico study of different cytoneme mechanism that control the Hh signaling pathway in different Drosophila tissues. We quantified different experimental magnitudes and behaviors to develop a well-founded multidisciplinary models to study mechanics such as cytoneme signaling or cytoneme guidance. The theoretical models proposed in this work were validated and posteriorly use to made prediction that helps into the understanding of different biological questions. The role of different cytonemes features have been clarify identifying variables and plausible mechanisms behind different aspect of cytoneme signaling. Finally, the computational implementation of the models was designed as general tools that can be easily revise accordingly to new discoveries in the field. Due to their generality they can be also extrapolated to other biological systems.