Characterizing the effects of Robinow Syndrome-associated Dishevelled1 variants in cell signalling and development in fruit fly model

Studying developmental disorders sheds light on how signalling networks regulate development. Our research focuses on the Dishevelled 1 (DVL1) variant DVL11519ΔT, found in Autosomal Dominant Robinow Syndrome (RS) patients. RS is a rare disorder linked to mutations in genes involved in the noncanonical/Planar Cell Polarity pathway of Wnt signalling, essential for tissue homeostasis and development. DVL1 acts in both canonical and noncanonical Wnt pathways. The variant DVL11519ΔT has a frameshift mutation replacing the C-terminus with a novel peptide. We used the Gal4-UAS system to study its effects in fruit flies, comparing wildtype and variant DVL1. Our results show that the variant alters tissue morphology, induces apoptosis, and disrupts wing development. RNA-seq revealed differential gene expression related to developmental processes. Our investigation with C-terminal truncated DVL1 constructs found that the novel peptide, rather than the loss of the C-terminus, drives these changes. This research advances our understanding of RS and DVL1 function.