Prof Natasha Harvey, University of South Australia

Prof Natasha Harvey | Director, Centre for Cancer Biology | UniSA, SA Pathology

Defining the genetic and developmental basis of human lymphatic vascular disease

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. While defects in the development and function of lymphatic vessels have long been recognised to underlie lymphatic vascular anomalies and primary lymphoedema, new roles for lymphatic vessels in pathological conditions including atherosclerosis, glaucoma and neurodegenerative diseases are rapidly emerging. 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) (Kazenwadel et al.,Blood, 2012, Ostergaard et al., Nat Gen, 2011). This discovery was the first to demonstrate an important role for GATA2in the lymphatic vasculature. We subsequently determined that Gata2 is crucial for lymphatic vascular development by orchestrating the construction and maintenance of lymphatic vessel valves (Kazenwadel et al., J Clin Invest, 2015). Our current work is focussed on defining the transcriptional 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 (Betterman et al., J Clin Invest, 2020). 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.

Speaker bio:

Professor Natasha Harvey is Director of the Centre for Cancer Biology, University of South Australia and SA Pathology. Natasha received her PhD from the University of Adelaide and undertook postdoctoral training in the laboratory of Guillermo Oliver at St Jude Children’s Research Hospital, USA. Here, she focussed on defining the role of the homeobox transcription factor PROX1 in lymphatic vascular development. In 2005, she returned to Adelaide to establish her independent research program. 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.

 

Hosted by: Prof Leonie Quinn