Pkd1 and Wnt5a genetically interact to control lymphatic vascular morphogenesis in mice

Lymphatic vascular development is regulated by well-characterised signalling and transcriptional pathways. These pathways regulate lymphatic endothelial cell (LEC) migration, motility, polarity and and morphogenesis. Canonical and non-canonical WNT signalling pathways are known to control LEC polarity and development of lymphatic vessels and valves. PKD1, encoding Polycystin-1, is the most commonly mutated gene in polycystic kidney disease but has also been shown to be essential in lymphatic vascular morphogenesis. The mechanism by which Pkd1 acts during lymphangiogenesis remains unclear. Here we find that loss of non-canonical WNT signalling components Wnt5a and Ryk phenocopy lymphatic defects seen in Pkd1 knockout mice. To investigate genetic interaction, we generated Pkd1/Wnt5a double knockout mice. Loss of Wnt5a suppressed phenotypes seen in the lymphatic vasculature of Pkd1-/- mice and Pkd1 deletion suppressed phenotypes observed in Wnt5a-/- mice. Thus, we report mutually suppressive roles for Pkd1 and Wnt5a, with developing lymphatic networks restored to a more wild-type state in double mutant mice. This genetic interaction between Pkd1 and the non-canonical WNT signalling pathway ultimately controls LEC polarity and the morphogenesis of developing vessel networks. Our work suggests that Pkd1 acts at least in part by regulating non-canonical WNT signalling during the formation of lymphatic vascular networks.

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Vascular endothelial cell specification in health and disease

Angiogenesis ◽

10.1007/s10456-021-09785-7 ◽

2021 ◽

Author(s):

Corina Marziano ◽

Gael Genet ◽

Karen K. Hirschi

Keyword(s):

Endothelial Cells ◽

Endothelial Cell ◽

Current Knowledge ◽

Vascular Malformations ◽

Immune Surveillance ◽

Vascular Endothelial Cell ◽

Lymphatic Vessels ◽

Lymphatic Endothelial Cell ◽

The Body ◽

Vascular Networks

AbstractThere are two vascular networks in mammals that coordinately function as the main supply and drainage systems of the body. The blood vasculature carries oxygen, nutrients, circulating cells, and soluble factors to and from every tissue. The lymphatic vasculature maintains interstitial fluid homeostasis, transports hematopoietic cells for immune surveillance, and absorbs fat from the gastrointestinal tract. These vascular systems consist of highly organized networks of specialized vessels including arteries, veins, capillaries, and lymphatic vessels that exhibit different structures and cellular composition enabling distinct functions. All vessels are composed of an inner layer of endothelial cells that are in direct contact with the circulating fluid; therefore, they are the first responders to circulating factors. However, endothelial cells are not homogenous; rather, they are a heterogenous population of specialized cells perfectly designed for the physiological demands of the vessel they constitute. This review provides an overview of the current knowledge of the specification of arterial, venous, capillary, and lymphatic endothelial cell identities during vascular development. We also discuss how the dysregulation of these processes can lead to vascular malformations, and therapeutic approaches that have been developed for their treatment.

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Exaggerated behavioral phenotypes in Fmr1/Fxr2 double knockout mice reveal a functional genetic interaction between Fragile X-related proteins

Human Molecular Genetics ◽

10.1093/hmg/ddl121 ◽

2006 ◽

Vol 15 (12) ◽

pp. 1984-1994 ◽

Cited By ~ 81

Author(s):

Corinne M. Spencer ◽

Ekaterina Serysheva ◽

Lisa A. Yuva-Paylor ◽

Ben A. Oostra ◽

David L. Nelson ◽

...

Keyword(s):

Knockout Mice ◽

Genetic Interaction ◽

Fragile X ◽

Double Knockout ◽

Behavioral Phenotypes ◽

Related Proteins

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Growth arrest of PPP2R5C and PPP2R5D double knockout mice indicates a genetic interaction and conserved function for these PP2A B subunits

FASEB BioAdvances ◽

10.1096/fba.2021-00130 ◽

2021 ◽

Author(s):

Jade J. Dyson ◽

Fatima Abbasi ◽

Prajakta Varadkar ◽

Brent McCright

Keyword(s):

Knockout Mice ◽

Genetic Interaction ◽

Growth Arrest ◽

Double Knockout ◽

B Subunits

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Non-canonical Wnt signalling modulates the endothelial shear stress flow sensor in vascular remodelling

eLife ◽

10.7554/elife.07727 ◽

2016 ◽

Vol 5 ◽

Cited By ~ 63

Author(s):

Claudio A Franco ◽

Martin L Jones ◽

Miguel O Bernabeu ◽

Anne-Clemence Vion ◽

Pedro Barbacena ◽

...

Keyword(s):

Endothelial Cells ◽

Wnt Signalling ◽

Low Flow ◽

Vascular Networks ◽

Lower Shear ◽

Physical Forces ◽

Axial Polarization ◽

And Migration ◽

Canonical Wnt ◽

Molecular Signals

Endothelial cells respond to molecular and physical forces in development and vascular homeostasis. Deregulation of endothelial responses to flow-induced shear is believed to contribute to many aspects of cardiovascular diseases including atherosclerosis. However, how molecular signals and shear-mediated physical forces integrate to regulate vascular patterning is poorly understood. Here we show that endothelial non-canonical Wnt signalling regulates endothelial sensitivity to shear forces. Loss of Wnt5a/Wnt11 renders endothelial cells more sensitive to shear, resulting in axial polarization and migration against flow at lower shear levels. Integration of flow modelling and polarity analysis in entire vascular networks demonstrates that polarization against flow is achieved differentially in artery, vein, capillaries and the primitive sprouting front. Collectively our data suggest that non-canonical Wnt signalling stabilizes forming vascular networks by reducing endothelial shear sensitivity, thus keeping vessels open under low flow conditions that prevail in the primitive plexus.

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