Mouse Wnt receptor gene Fzd5 is essential for yolk sac and placental angiogenesis

Abstract

Wnts are secreted signaling molecules implicated in various developmental processes and frizzled proteins are the receptors for these Wnt ligands. To investigate the physiological roles of frizzled proteins, we isolated and characterized a novel mouse frizzled gene Fzd5. Fzd5 mRNA was expressed in the yolk sac, eye and lung bud at 9.5 days post coitum. Fzd5 specifically synergized with Wnt2, Wnt5a and Wnt10b in ectopic axis induction assays in Xenopus embryos. Using homologous recombination in embryonic stem cells, we have generated Fzd5 knockout mice. While the heterozygotes were viable, fertile and appeared normal, the homozygous embryos died in utero around 10.75 days post coitum, owing to defects in yolk sac angiogenesis. At 10.25 days post coitum, prior to any morphological changes, endothelial cell proliferation was markedly reduced in homozygous mutant yolk sacs, as measured by BrdU labeling. By 10.75 days post coitum, large vitelline vessels were poorly developed, and the capillary plexus was disorganized. At this stage, vasculogenesis in the placenta was also defective, although that in the embryo proper was normal. Because Wnt5a and Wnt10b co-localized with Fzd5 in the developing yolk sac, these two Wnts are likely physiological ligands for the Fzd5-dependent signaling for endothelial growth in the yolk sac.

FZD 5 is a Gα q -coupled receptor that exhibits the functional hallmarks of prototypical GPCRs

“…FZD 5 has been reported to interact with WNT-2, WNT-3, WNT-3A, WNT-5A, WNT-7A, WNT-7B, WNT-9B, WNT-10B, and WNT-11 in various cellular and developmental contexts, leading to numerous cellular outcomes that still require careful characterization at the molecular level (6)(7)(8)(9)(10)(11)(12)(13)(14)(15). Loss-of-function studies have revealed a role for FZD 5 in ocular development, whereas gain-of-function studies have demonstrated its role in synaptogenesis (11,16).…”

WNT5A Interacts With FZD5 and LRP5 to Regulate Proliferation and Self-Renewal of Endometrial Mesenchymal Stem-Like Cells

“…Although LRP5 protein is higher in unfractionated stromal cells than eMSC, FZD5 and LRP5 have coexpression in a significant proportion of the eMSC population, suggesting the possibility of FZD5-LRP5 interaction in eMSC maintenance. FZD5 is a common noncanonical WNT receptor (Ishikawa et al, 2001;Arderiu et al, 2014;Kim et al, 2019), and the blocking of WNT5A-FZD5 signaling pathway can inhibit the PKC pathway (Weeraratna et al, 2002). A recent study has demonstrated FZD5 as a regulator in the maintenance of human mesenchymal stem/ stromal cells (hMSCs) (Harada et al, 2021).…”

“…FZD5 is a common noncanonical WNT receptor ( Ishikawa et al, 2001 ; Arderiu et al, 2014 ; Kim et al, 2019 ), and the blocking of WNT5A–FZD5 signaling pathway can inhibit the PKC pathway ( Weeraratna et al, 2002 ). A recent study has demonstrated FZD5 as a regulator in the maintenance of human mesenchymal stem/stromal cells (hMSCs) ( Harada et al, 2021 ).…”

Vascular Smooth Muscle Cell Development and Cardiovascular Malformations

“…The highly conserved Wnt signaling axes regulate cell differentiation, apoptosis, and orientation. Deficiency in the Wnt receptor Frizzled-5 is embryonically lethal, as it severely impairs yolk sac angiogenesis [82] . Wnt3a promotes SMC differentiation by upregulating SM22-α in vitro [83] .…”

“…Deficiency in the Wnt receptor Frizzled-5 is embryonically lethal, as it severely impairs yolk sac angiogenesis. [82] Wnt3a promotes SMC differentiation by upregulating SM22-a in vitro. [83] Wnt7b is essential for pulmonary vascular smooth muscle integrity.…”