In the Hogan lab, researchers investigate the development of lymphatic vasculature and the blood brain barrier, which play important roles in the metastatic spread of cancer.
Specifically, we aim to:
- Characterise signalling and transcriptional mechanisms that control lymphangiogenesis using studies in zebrafish and mice.
- Discover new genes essential for development of the blood brain barrier using zebrafish genetics.
- Develop imaging methods to visualise signalling in real time during tissue morphogenesis.
- Model cellular pathologies of vasculature in cancer and vascular disease.
Molecular mechanisms controlling lymphangiogenesis
Lymphatic vessels form from pre-existing vessels via lymphangiogenesis in both development and pathological settings. Lymphatics function to drain tissue fluid and traffic immune cells, but are also utilised by tumours to metastasise to lymph nodes and secondary sites. We characterise molecular mechanisms that control lymphangiogenesis using model organisms (zebrafish and mice). We use large scale genetic screens, CRISPR genome editing, transgenesis, single cell genomics and in vivo cell biology.
Current work includes analysis of the role of Yap1 and the Hippo pathway in endothelial cell proliferation and expansion of lymphatic networks, the study of alternative pre-mRNA splicing controlled by Nova2 in lymphatic vascular signalling and the analysis of lymphatic endothelial cell fate specification. Many of our studies converge on the central CCBE1/VEGFC/VEGFR3 pathway, which plays important roles in development and disease.
Genetics of blood brain barrier formation
The blood brain barrier (BBB) separates the brain parenchyma from circulating blood and macromolecules, represents a significant challenge for delivery of cancer therapeutics, and acts as a barrier in metastasis. The BBB is made up of tightly adherent vascular endothelial cells surrounded by essential mural cell lineages, such as pericytes. How the different cells at the BBB develop, interact and function in homeostasis and disease, as well as how they can be manipulated for therapeutic gain, remains far from understood. We are undertaking a large scale forward genetic screen using zebrafish to discover genes and molecular mechanisms that control the maturation and function of pericytes and BBB endothelial cells. This work aims to identify new molecular mechanisms and therapeutic opportunities.
Live imaging of cellular signalling in vascular development and disease models
Directly observing key molecules and pathways as they act to control tissue formation, or as they drive pathological phenotypes, is a major challenge that is rapidly becoming a reality. We are developing biosensors that report signalling downstream of CCBE1/VEGFC/VEGFR3 activation, including a reporter of Erk activity. This allows us to see real-time dynamic pathway activation in the context of tissue and cellular interactions in normal development and disease models. This work has uncovered unexpected mechanisms in angiogenesis during wound repair and allowed us to study cell-cell adhesion mechanics in developing tissues. We are currently diversifying our biosensor tools and applying these imaging approaches to cellular resolution studies of lymphangiogenesis, the BBB, lymphatic malformation and metastatic cellular interactions.
Baek, S, Oh, TG, Secker, G, Sutton, DL, Okuda, KS, Paterson, S, Bower, NI, Toubia, J, Koltowska, K, Capon, SJ, Baillie, GJ, Simons, C, Muscat, GEO, Lagendijk, AK, Smith, KA, Harvey, NL, Hogan, BM, (2019), The Alternative Splicing Regulator Nova2 Constrains Vascular Erk Signaling to Limit Specification of the Lymphatic Lineage. Developmental Cell, 2019 Apr 22;49(2):279-292.
Grimm L, Nakajima H, Chaudhury S, Bower NI, Okuda KS, Cox AG, Harvey NL, Koltowska K, Mochizuki N, Hogan BM. (2019) Yap1 promotes sprouting and proliferation of lymphatic progenitors downstream of Vegfc in the zebrafish trunk. Elife. Apr 30;8
Bower, NI, Koltowska, K, Pichol-Thievend, C, Virshup, I, Paterson, S, Lagendijk, AK, Wang, W, Lindsey, BW, Bent, SJ, Baek, S, Rondon-Galeano, M, Hurley, DG, Mochizuki, N, Simons, C, Francois, M, Wells, CA, Kaslin, J, Hogan, BM (2017), Mural lymphatic endothelial cells regulate meningeal angiogenesis in the zebrafish. Nature Neuroscience, vol. 20, no. 6, pp. 774-783
Lagendijk, AK, Gomez, GA, Baek, S, Hesselson, D, Hughes, WE, Paterson, S, Conway, DE, Belting, H, Affolter, M, Smith, KA, Schwartz, MA, Yap, AS, Hogan, BM (2017), ‘Live imaging molecular changes in junctional tension upon VE-cadherin in zebrafish’, Nature Communications, vol. 8, no. 1, doi:10.1038/s41467-017-01325-6,
De Angelis, JE, Lagendijk, AK, Chen, H, Tromp, A, Bower, NI, Tunny, KA, Brooks, AJ, Bakkers, J, Francois, M, Yap, AS, Simons, C, Wicking, C, Hogan, BM#, Smith, KA# (2017), ‘Tmem2 Regulates Embryonic Vegf Signaling by Controlling Hyaluronic Acid Turnover’, Developmental Cell, vol. 40, no. 2, pp. 123-136.
Koltowska, K, Paterson, S, Bower, NI, Baillie, GJ, Lagendijk, AK, Astin, JW, Chen, H, Francois, M, Crosier, PS, Taft, RJ, Simons, C, Smith, KA, Hogan, BM (2015), ‘mafba is a downstream transcriptional effector of Vegfc signaling essential for embryonic lymphangiogenesis in zebrafish’, Genes & Development, vol. 29, no. 15, pp. 1618-1630
Alders M, Hogan BM, Gjini E, Salehi F, Al-Gazali L, Hennekam EA, Holmberg EE, Mannens MM, Mulder MF, Offerhaus GJ, Prescott TE, Schroor EJ, Verheij JB, Witte M, Zwijnenburg PJ, Vikkula M, Schulte-Merker S, Hennekam RC. (2009). ‘Mutations in CCBE1 cause generalized lymph vessel dysplasia in humans’. Nature Genetics. Dec; 41(12):1272-4.
Hogan, BM, Bos, FL, Bussmann, J, Witte, M, Chi, NC, Duckers, HJ, Schulte-Merker, S (2009), ‘ccbe1 is required for embryonic lymphangiogenesis and venous sprouting’, Nature Genetics, Apr; vol. 41, no. 4, pp. 396-398
Hogan BM and Schulte-Merker S. How to plumb a pisces: understanding vascular development and disease using zebrafish embryos. Developmental Cell. 2017 Sep 25; 42(6):567-583.
Koltowska K, Betterman KL, Harvey NL, Hogan BM. Getting out and about: the emergence and morphogenesis of the vertebrate lymphatic vasculature. Development. 2013 May; 140(9):1857-70.
Currently seeking motivated Honours and PhD students with interests in developmental biology, cell biology, genetics and disease modelling.