Lymphatic Development Laboratory
Research Program Overview:
Lymphatic vessels are a crucial but often overlooked component of the cardiovascular system. These specialised vessels return fluid and proteins from our tissues to the bloodstream, absorb lipids from the digestive tract, and direct the trafficking of immune cells throughout our bodies, thereby controlling immunity. Abnormalities in the development or function of lymphatic vessels are associated with human disorders including vascular malformations, lymphoedema, inflammatory diseases, neurological disorders and cancer. Despite the integral role played by lymphatic vessels in health and disease, little is known about the genes and signals that direct their construction.
Our research seeks to understand how the lymphatic vessels are built during development and how this process goes wrong in human disease states. We investigate mouse and human genetics in addition to cell, molecular and developmental biology, in order to define the genes and signalling pathways that underpin lymphatic development and function in health and disease. We are particularly interested in understanding the genetic and developmental basis of human lymphatic diseases, defining how the identity of cells in the lymphatic system is programmed during development and investigating the process by which lymphatic vessel valves are built. Our ultimate aim is that by understanding these processes, we will be able to develop more effective treatments for patients affected by lymphatic vascular disease.
Current Research Projects:
- Defining the genetic and developmental basis of human lymphatic vascular disorders including lymphatic vascular malformations and lymphoedema.
- Understanding how lymphatic vessel identity is programmed by transcription factors.
- Characterising the function of novel genes in lymphatic vessel growth and development.
- Defining the genes and signalling pathways important for lymphatic vessel valve development.
- High resolution imaging of lymphatic vessel growth and development.
Select Recent Publications:
- Byrne AB, Brouillard P, Sutton DL, Kazenwadel J, Montazaribarforoushi S, Secker GA, Oszmiana A, Babic M, Betterman KL, Brautigan PJ, White M, Piltz SG, Thomas PQ, Hahn CN, Rath M, Felbor U, Korenke GC, Smith CL, Wood KH, Sheppard SE, Adams D, Kariminejad A, Helaers R, Boon LM, Revencu N, Moore L, Barnett C, Haan E, Arts P, Vikkula M*, Scott HS* and Harvey NL*. Pathogenic variants in MDFIC cause recessive central conducting lymphatic anomaly with lymphedema. Sci Transl Med, In press, 2022. * Equal senior author.
- Francois M, Oszmiana A and Harvey NL. Where form meets function: the cells and signals that shape the lymphatic vasculature during development. 148(11):dev167098, 2021.
- Oliver G, Kipnis J, Randolph GJ and Harvey NL. The lymphatic vasculature in the 21st century: Novel functional roles in health and disease. 182(2):270-96, 2020.
- Betterman KL, Sutton DL, Secker GA, Kazenwadel J, Oszmiana A, Lim L, Miura N, Sorokin L, Hogan BM, Kahn ML, McNeill H and Harvey NL. Atypical cadherin FAT4 orchestrates lymphatic endothelial cell polarity in response to flow. J Clin Invest. 130(6):3315-28, 2020.
- Pichol-Thievend C, Betterman KL, Liu X, Ma W, Skoczylas R, Lesieur E, Bos FL, Schulte D, Schulte-Merker S, Hogan BM, Oliver G, Harvey NL* and Francois M*. A blood capillary plexus-derived population of progenitor cells contributes to genesis of the dermal lymphatic vasculature during embryonic development. Development. May 17;145(10), 2018. * Equal senior author
- Betterman KL and Harvey NL. The lymphatic vasculature: development and role in shaping immunity. Immunol Rev. 271(1):276-92, 2016.
- Kazenwadel J, Betterman KL, Chong CE, Stokes PH, Lee YK, Secker GA, Agalarov Y, Demir CS, Lawrence DM, Sutton DL, Tabruyn SP, Miura N, Salminen M, Petrova TV, Matthews JM, Hahn SN, Scott HS and Harvey NL. GATA2 is required for lymphatic vessel valve development and maintenance. J Clin Invest. 125(8):2979-94, 2015.
- Betterman KL, Paquet-Fifield S, Asselin-Labat, ML, Visvader JE, Butler LM, Stacker SA, Achen MA and Harvey NL. Remodeling of the lymphatic vasculature during mouse mammary gland morphogenesis is mediated via epithelial derived lymphangiogenic stimuli. Am J Pathol. 181: 2225-38, 2012.
- Kazenwadel J, Secker GA, Liu YJ, Rosenfeld JA, Wildin RS, Cuellar-Rodriguez J, Hsu AP, Dyack S, Fernandez CV, Chong CE, Babic M, Bardy PG, Shimamura A, Zhang MY, Walsh T, Holland SM, Hickstein DD, Horwitz MS, Hahn CN, Scott HS* and Harvey NL*. Loss-of-function germline GATA2 mutations in patients with MDS/AML or MonoMAC syndrome and primary lymphedema reveal a key role for GATA2 in the lymphatic vasculature. 119: 1283-91, 2012. * Equal senior author
- Gordon EJ, Rao S, Pollard JW, Nutt SL, Lang RA and Harvey NL. Macrophages define dermal lymphatic vessel caliber during development by regulating lymphatic endothelial cell proliferation. 137: 3899-910, 2010.
- Kazenwadel J, Michael MZ and Harvey NL. Prox1 expression is negatively regulated by miR-181 in endothelial cells. 116: 2395-401, 2010.