Fusing VE-Cadherin to α-Catenin Impairs Fetal Liver Hematopoiesis and Lymph but Not Blood Vessel Formation

Abstract

We have recently shown that genetic replacement of VE-cadherin by a VE-cadherin-␣-catenin fusion construct strongly impairs opening of endothelial cell contacts during leukocyte extravasation and induction of vascular permeability in adult mice. Here we show that this mutation leads to lethality at midgestation on a clean C57BL/6 background. Investigating the reasons for embryonic lethality, we observed a lack of fetal liver hematopoiesis and severe lymphedema but no detectable defects in blood vessel formation and remodeling. As for the hematopoiesis defect, VE-cadherin-␣-catenin affected neither the generation of hematopoietic stem and progenitor cells (HSPCs) from hemogenic endothelium nor their differentiation into multiple hematopoietic lineages. Instead, HSPCs accumulated in the fetal circulation, suggesting that their entry into the fetal liver was blocked. Edema formation was caused by disturbed lymphatic vessel development. Lymphatic progenitor cells of VE-cadherin-␣-catenin-expressing embryos were able to leave the cardinal vein and migrate to the site of the first lymphatic vessel formation, yet subsequently, these cells failed to form large lumenized lymphatic vessels. Thus, stabilizing endothelial cell contacts by a covalent link between VE-cadherin and ␣-catenin affects recruitment of hematopoietic progenitors into the fetal liver and the development of lymph but not blood vessels.

GATA4-dependent organ-specific endothelial differentiation controls liver development and embryonic hematopoiesis

“…Notably, it has been shown that artificial junctional tightening by overexpression of a VE-cadherin/α-catenin fusion protein in EC impaired immigration into the nascent hematopoietic stem cell niche in the liver in a very similar manner (41,42). Thus, low-level endothelial junctional stability is an indispensable requirement for HSC immigration into the fetal liver.…”

Nuclear Signaling from Cadherin Adhesion Complexes

“…Evidence that β-catenin is both a critical component of the cadherin/catenin adhesive complex, serving as an important linker between the cadherin and the actin-binding protein, α-catenin (Dartsch, Schulte, Hagerling, Kiefer, & Vestweber, 2014), and an indispensible mediator of Wnt signaling raises intriguing questions as to whether or not adhesion and Wnt signaling are coordinated through the use of this common component, β-catenin. Indeed, experimental manipulations in cells and simple model organisms reveal that cadherin expression and β-catenin signaling are interrelated.…”

DLL4 promotes continuous adult intestinal lacteal regeneration and dietary fat transport

“…Previous studies of BECs demonstrated that dynamic remodeling of VE-cadherin is a prerequisite for efficient tip cell positioning (68). Furthermore, stabilization of endothelial cell-cell contacts in mice bearing VE-cadherin fused with α-catenin strongly impairs formation of lymphatic vessels during embryogenesis (69). Thus, abnormal stabilization of adherens junctions may both underlie the inability of Dll4-deficient LECs to efficiently migrate to occupy the tip cell position and, at the same time, lead to the impairment of chylomicron uptake and reduction of lacteal transport capacity.…”