Defining the genetic and developmental basis of human lymphatic vascular disease

Associate Professor Natasha Harvey
Centre for Cancer Biology
SA Pathology and University of South Australia

Abstract: Lymphatic vessels are an integral component of the cardiovascular system. These specialised vessels play key roles in fluid homeostasis, dietary lipid absorption and the regulation of immune cell trafficking. We and others recently demonstrated that heterozygous germline mutations in the zinc finger transcription factor GATA2 underlie Emberger syndrome, a disorder characterised by lymphedema and predisposition to myelodysplastic syndrome/acute myeloid leukemia (MDS/AML) . This discovery was the first to demonstrate an important role for GATA2 in the lymphatic vasculature. We subsequently determined that Gata2 is crucial for lymphatic vascular development by orchestrating the construction and maintenance of lymphatic vessel valves. Our current work aims to define the mechanisms by which GATA2 controls valve morphogenesis in the lymphatic vasculature. We have identified both GATA2-bound transcriptional regulatory elements and GATA2 target genes important for valve development, some of which are also mutated in human lymphoedema syndromes. These genes and their roles in lymphatic vessel morphogenesis will be discussed. Ultimately, understanding the genetic basis of lymphoedema will inform our knowledge of the cellular events and signalling pathways important for building functional lymphatic vessels, information that will underpin the design of novel, targeted therapeutics able to promote lymphatic vessel function and treat lymphoedema. 

Bio: Associate Professor Natasha Harvey is Head of the Lymphatic Development Laboratory at the Centre for Cancer Biology, UniSA and SA Pathology. Natasha received her PhD from the University of Adelaide for studies performed in Sharad Kumar’s laboratory that investigated caspase-2 activation during apoptosis. Following two years as a postdoctoral fellow with Sharad, during which time she cloned a novel Drosophila caspase, Natasha undertook postdoctoral training in the laboratory of Guillermo Oliver at St Jude Children’s Research Hospital, Memphis, USA. Here, she spent four years studying mouse embryonic lymphatic vascular development, in particular defining the role of the homeobox transcription factor PROX1 in lymphatic vascular development. In 2005, she was awarded a Florey Fellowship to return to Adelaide and establish her independent research program at the Centre for Cancer Biology. Natasha’s work aims to understand how the lymphatic vasculature is constructed during development and how this process “goes wrong” in human lymphatic vessel pathologies. Her work in this field has been published in journals including Blood, Development and The Journal of Clinical Investigation.