Lymphangiogenesis is a dynamic process that involves the directed migration of lymphatic endothelial cells (LECs) to form lymphatic vessels. The molecular mechanisms that underpin lymphatic vessel patterning are not fully elucidated and, to date, no global regulator of lymphatic vessel guidance is known. In this study, we identify the transmembrane cell signalling receptor Plexind1 as a negative regulator of both lymphatic vessel guidance and lymphangiogenesis in zebrafish. plxnd1 is expressed in developing lymphatics and is required for the guidance of both the trunk and facial lymphatic networks. Loss of plxnd1 is associated with misguided intersegmental lymphatic vessel growth and aberrant facial lymphatic branches. Lymphatic guidance in the trunk is mediated, at least in part, by the Plxnd1 ligands, Semaphorin3aa and Semaphorin3c. Finally, we show that Plxnd1 normally antagonises Vegfr/Erk signalling to ensure the correct number of facial LECs and that loss of plxnd1 results in facial lymphatic hyperplasia. As a global negative regulator of lymphatic vessel development, the Sema/Plxnd1 signalling pathway is a potential therapeutic target to treat diseases associated with dysregulated lymphatic growth.
Plexind1 negatively regulates zebrafish lymphatic development
- Award Group:
- Funder(s): National Institutes of Health
- Award Id(s): 5R01HL133687
- Funder(s):
- Award Group:
- Funder(s): Health Research Council of New Zealand
- Award Id(s): 14/105
- Funder(s):
- Award Group:
- Funder(s): Marsden Fund
- Award Id(s): UOA1602
- Funder(s):
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- Accepted Manuscript 07 October 2022
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Denver D. Britto, Jia He, June P. Misa, Wenxuan Chen, Purvi M. Kakadia, Lin Grimm, Caitlin D. Herbert, Kathryn E. Crosier, Philip S. Crosier, Stefan K. Bohlander, Benjamin M. Hogan, Christopher J. Hall, Jesús Torres-Vázquez, Jonathan W. Astin; Plexind1 negatively regulates zebrafish lymphatic development. Development 2022; dev.200560. doi: https://doi.org/10.1242/dev.200560
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