@phdthesis{Fontana2020,
  author    = {Fontana, Federica},
  title     = {Antagonistic activities of Vegfr3/Flt4 and Notch1b fine-tune mechanosensitive signaling during zebrafish cardiac valvulogenesis},
  doi       = {10.25932/publishup-48751},
  url       = {http://nbn-resolving.de/urn:nbn:de:kobv:517-opus4-487517},
  school      = {Universit{\"a}t Potsdam},
  pages     = {III, 110},
  year      = {2020},
  abstract  = {Cardiac valves are essential for the continuous and unidirectional flow of blood throughout the body. During embryonic development, their formation is strictly connected to the mechanical forces exerted by blood flow. The endocardium that lines the interior of the heart is a specialized endothelial tissue and is highly sensitive to fluid shear stress. Endocardial cells harbor a signal transduction machinery required for the translation of these forces into biochemical signaling, which strongly impacts cardiac morphogenesis and physiology. To date, we lack a solid understanding on the mechanisms by which endocardial cells sense the dynamic mechanical stimuli and how they trigger different cellular responses. In the zebrafish embryo, endocardial cells at the atrioventricular canal respond to blood flow by rearranging from a monolayer to a double-layer, composed of a luminal cell population subjected to blood flow and an abluminal one that is not exposed to it. These early morphological changes lead to the formation of an immature valve leaflet. While previous studies mainly focused on genes that are positively regulated by shear stress, the mechanisms regulating cell behaviors and fates in cells that lack the stimulus of blood flow are largely unknown. One key discovery of my work is that the flow-sensitive Notch receptor and Kr{\"u}ppel-like factor (Klf) 2, one of the best characterized flow-regulated transcriptional factors, are activated by shear stress but that they function in two parallel signal transduction pathways. Each of these two pathways is essential for the rearrangement of atrioventricular cells into an immature double-layered valve leaflets. A second key discovery of my study is the finding that both Notch and Klf2 signaling negatively regulate the expression of the angiogenesis receptor Vegfr3/Flt4, which becomes restricted to abluminal endocardial cells of the valve leaflet. Within these cells, Flt4 downregulates the expressions of the cell adhesion proteins Alcam and VE-cadherin. A loss of Flt4 causes abluminal endocardial cells to ectopically express Notch, which is normally restricted to luminal cells, and impairs valve morphology. My study suggests that abluminal endocardial cells that do not experience mechanical stimuli loose Notch expression and this triggers expression of Flt4. In turn, Flt4 negatively regulates Notch on the abluminal side of the valve leaflet. These antagonistic signaling activities and fine-tuned gene regulatory mechanisms ultimately shape cardiac valve leaflets by inducing unique differences in the fates of endocardial cells.},
  language  = {en}
}
@article{PaoliniFontanaVanCuongPhametal.2021,
  author    = {Paolini, Alessio and Fontana, Federica and Van-Cuong Pham, and R{\"o}del, Claudia Jasmin and Seyfried, Salim},
  title     = {Mechanosensitive Notch-Dll4 and Klf2-Wnt9 signaling pathways intersect in guiding valvulogenesis in zebrafish},
  series = {Cell reports},
  volume    = {37},
  journal   = {Cell reports},
  number    = {1},
  publisher = {Cell Press},
  address   = {Maryland Heights, MO},
  issn      = {2211-1247},
  doi       = {10.1016/j.celrep.2021.109782},
  pages     = {13},
  year      = {2021},
  abstract  = {In the zebrafish embryo, the onset of blood flow generates fluid shear stress on endocardial cells, which are specialized endothelial cells that line the interior of the heart. High levels of fluid shear stress activate both Notch and Klf2 signaling, which play crucial roles in atrioventricular valvulogenesis. However, it remains unclear why only individual endocardial cells ingress into the cardiac jelly and initiate valvulogenesis. Here, we show that lateral inhibition between endocardial cells, mediated by Notch, singles out Delta-like-4-positive endocardial cells. These cells ingress into the cardiac jelly, where they form an abluminal cell population. Delta-like-4-positive cells ingress in response to Wnt9a, which is produced in parallel through an Erk5Klf2-Wnt9a signaling cascade also activated by blood flow. Hence, mechanical stimulation activates parallel mechanosensitive signaling pathways that produce binary effects by driving endocardial cells toward either luminal or abluminal fates. Ultimately, these cell fate decisions sculpt cardiac valve leaflets.},
  language  = {en}
}