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FZD2 regulates limb development by mediating β-catenin-dependent and -independent Wnt signaling pathways

Authors :
Xuming Zhu
Mingang Xu
N. Adrian Leu
Edward E. Morrisey
Sarah E. Millar
Source :
Disease Models & Mechanisms. 16
Publication Year :
2023
Publisher :
The Company of Biologists, 2023.

Abstract

Human Robinow syndrome (RS) and dominant omodysplasia type 2 (OMOD2), characterized by skeletal limb and craniofacial defects, are associated with heterozygous mutations in the Wnt receptor FZD2. However, as FZD2 can activate both canonical and non-canonical Wnt pathways, its precise functions and mechanisms of action in limb development are unclear. To address these questions, we generated mice harboring a single-nucleotide insertion in Fzd2 (Fzd2em1Smill), causing a frameshift mutation in the final Dishevelled-interacting domain. Fzd2em1Smill mutant mice had shortened limbs, resembling those of RS and OMOD2 patients, indicating that FZD2 mutations are causative. Fzd2em1Smill mutant embryos displayed decreased canonical Wnt signaling in developing limb mesenchyme and disruption of digit chondrocyte elongation and orientation, which is controlled by the β-catenin-independent WNT5A/planar cell polarity (PCP) pathway. In line with these observations, we found that disruption of FZD function in limb mesenchyme caused formation of shortened bone elements and defects in Wnt/β-catenin and WNT5A/PCP signaling. These findings indicate that FZD2 controls limb development by mediating both canonical and non-canonical Wnt pathways and reveal causality of pathogenic FZD2 mutations in RS and OMOD2 patients.

Details

ISSN :
17548411 and 17548403
Volume :
16
Database :
OpenAIRE
Journal :
Disease Models & Mechanisms
Accession number :
edsair.doi...........1a760577f09603c3eb884190833aa481
Full Text :
https://doi.org/10.1242/dmm.049876