Anatomy and Neuroscience - Research Publications

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Author: Mason, Elizabeth × Author: Hogan, Benjamin ×

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    Single-cell analysis of lymphatic endothelial cell fate specification and differentiation during zebrafish development
    Grimm, L ; Mason, E ; Yu, H ; Dudczig, S ; Panara, V ; Chen, T ; Bower, N ; Paterson, S ; Galeano, MR ; Kobayashi, S ; Senabouth, A ; Lagendijk, AK ; Powell, J ; Smith, KA ; Okuda, KS ; Koltowska, K ; Hogan, BM (WILEY, 2023-06-01)
    During development, the lymphatic vasculature forms as a second network derived chiefly from blood vessels. The transdifferentiation of embryonic venous endothelial cells (VECs) into lymphatic endothelial cells (LECs) is a key step in this process. Specification, differentiation and maintenance of LEC fate are all driven by the transcription factor Prox1, yet the downstream mechanisms remain to be elucidated. We here present a single-cell transcriptomic atlas of lymphangiogenesis in zebrafish, revealing new markers and hallmarks of LEC differentiation over four developmental stages. We further profile single-cell transcriptomic and chromatin accessibility changes in zygotic prox1a mutants that are undergoing a LEC-VEC fate shift. Using maternal and zygotic prox1a/prox1b mutants, we determine the earliest transcriptomic changes directed by Prox1 during LEC specification. This work altogether reveals new downstream targets and regulatory regions of the genome controlled by Prox1 and presents evidence that Prox1 specifies LEC fate primarily by limiting blood vascular and haematopoietic fate. This extensive single-cell resource provides new mechanistic insights into the enigmatic role of Prox1 and the control of LEC differentiation in development.
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    Live-imaging of endothelial Erk activity reveals dynamic and sequential signalling events during regenerative angiogenesis
    Okuda, KS ; Keyser, M ; Gurevich, DB ; Sturtzel, C ; Mason, EA ; Patterson, S ; Chen, H ; Scott, M ; Condon, ND ; Martin, P ; Distel, M ; Hogan, BM (ELIFE SCIENCES PUBLICATIONS LTD, 2021-05-18)
    The formation of new blood vessel networks occurs via angiogenesis during development, tissue repair, and disease. Angiogenesis is regulated by intracellular endothelial signalling pathways, induced downstream of vascular endothelial growth factors (VEGFs) and their receptors (VEGFRs). A major challenge in understanding angiogenesis is interpreting how signalling events occur dynamically within endothelial cell populations during sprouting, proliferation, and migration. Extracellular signal-regulated kinase (Erk) is a central downstream effector of Vegf-signalling and reports the signalling that drives angiogenesis. We generated a vascular Erk biosensor transgenic line in zebrafish using a kinase translocation reporter that allows live-imaging of Erk-signalling dynamics. We demonstrate the utility of this line to live-image Erk activity during physiologically relevant angiogenic events. Further, we reveal dynamic and sequential endothelial cell Erk-signalling events following blood vessel wounding. Initial signalling is dependent upon Ca2+ in the earliest responding endothelial cells, but is independent of Vegfr-signalling and local inflammation. The sustained regenerative response, however, involves a Vegfr-dependent mechanism that initiates concomitantly with the wound inflammatory response. This work reveals a highly dynamic sequence of signalling events in regenerative angiogenesis and validates a new resource for the study of vascular Erk-signalling in real-time.