Variants in frizzled 2 (FZD2), a receptor for the Wnt signalling pathway, are associated with a form of autosomal dominant Robinow Syndrome (AD-RS), a genetic disorder that presents with cleft palate and reduced long bones in the limbs. However, Fzd2-null mice do not recapitulate the limb phenotypes seen in human patients. Now, Rolf Stottmann and colleagues generate new mouse models using CRISPR/Cas9 and i-GONAD editing technologies that precisely model human variants with FZD2-associated AD-RS. By targeting the C-terminal Dishevelled-binding domain of FZD2, the authors generate several alleles that recapitulate cleft palate, limb shortening and perinatal lethality. Consistent with the role of FZD2 in Wnt signalling, the researchers observed that both canonical and non-canonical Wnt signalling activity is reduced using qPCR and by measuring chondrocyte cell length, respectively. Finally, the authors administer IIIC3a (a DKK inhibitor and canonical Wnt signalling agonist) in utero to show that, although embryos still develop a cleft palate, long bones significantly increase in length. Together, these data suggest that activation of canonical Wnt signalling may be sufficient to rescue long bone length in a mouse model of AD-RS and provide a therapeutic strategy for treating short limbs in human FZD2-associated AD-RS patients.
