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dc.contributor.advisorMedvinsky, Alexander
dc.contributor.advisorWilson, Val
dc.contributor.authorBinagui-Casas, Anahi Liliana
dc.date.accessioned2018-06-12T09:19:43Z
dc.date.available2018-06-12T09:19:43Z
dc.date.issued2018-07-09
dc.identifier.urihttp://hdl.handle.net/1842/31134
dc.description.abstractIn the mouse embryo, the first definitive haematopoietic stem cells (HSCs), capable of repopulating adult irradiated mice, emerge at mid-gestation by embryonic day E11. At this stage, the aorta-gonad-mesonephros (AGM) region is able to initiate and expand HSCs. Recently, it has been shown that the development of HSC in the AGM region results from the maturation of haematopoietic precursors called pre-HSCs. Mounting evidence points at an endothelial origin for these cells, the haematogenic endothelium. Analysis of VEGFs mutants, a critical pathway for endothelial developement, suggested that it also plays a role during early haematopoiesis. The main receptor of the pathway, FLK-1 (also known as VEGRR2 or KDR), is expressed in early hematopoietic and endothelial cells in the mouse embryo. Knock-out mutants for Flk-1 showed a decrease of endothelial and intra-embryonic haematopoietic progenitors. Although Flk-1 has been identified as an essential gene for HSC emergence, its exact point of action in HSC development remains unknown. In this thesis, I investigated the role of FLK-1 signalling in haematopoietic development and defined precise stages and cell types during HSC emergence in which FLK-1 is critically involved. by using a reporter line and antibody staining, I demonstrated that FLK-1 is expressed in the pre-HSCs/HSC lineage. Germ-line Flk-1 knockout results in embryonic lethality at around E9.0, before HSC emergence, mainly due to defects in vasculogenesis. Since arterial specification precedes HSC formation, it has never been elucidated whether the haematopoietic defects found in the knockouts are a secondary effect of the loss of vasculature or it FLK-1 is directly involved in haematopoietic specification. Therefore, to determine the role of the receptor in HSC development, I used a conditional inducible mutagenesis approach that allowed the deletion of Flk-1 precisely when pre-HSCs mature into HSCs at E10.5 and E11.5. My data showed that Flk-1 deletion at these stages affects both endothelial and haematopoietic progenitors, as well as HSCs. This suggests that the VEGF pathway is not only essential in early stages of haematopoietic development, as previously demonstrated, but it may be also involved in the maturation of pre HSC into HSCs at later stages.en
dc.contributor.sponsorEuropean Commissionen
dc.language.isoenen
dc.publisherThe University of Edinburghen
dc.relation.hasversionBatsivari, A., Rybtsov, S., Souilhol, C., Binagui-Casas, A., Hills, D., Zhao, S., Travers, P. & Medvinsky, A. (2017) 'Understanding hematopoietic stem cell development through functional correlation of their proliferative status with the Intra-aortic cluster architecture', Stem Cell Reports. DOI: 10.1016/j.stemcr.2017.04.003en
dc.relation.hasversionSouilhol, C., Gonzalez Lendinez, J., Rybtsov, S., Murphy, F., Wilson, H., Hills, D., Batsivari, A., Binagui-Casas, A., McGarvery, A., MacDonald, H.R., Kageyama, R., Siebel, C., Zhao, S. & Medvinsky, A., (2016), 'Developing HSCs become Notch independent by the end of maturation in the AGM region', Blood. DOI: 10.1182/blood-2016-03-708164en
dc.subjecthaematopoietic stem cellsen
dc.subjectaorta-gonad-mesonephros regionen
dc.subjectFLK-1en
dc.titleAnalysis of the role of Flk-1 during mouse haematopoietic stem cell developmenten
dc.typeThesis or Dissertationen
dc.type.qualificationlevelDoctoralen
dc.type.qualificationnamePhD Doctor of Philosophyen
dc.rights.embargodate2019-07-09en
dcterms.accessRightsRestricted Accessen


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