View Program - 63rd Annual Drosophila Research Conference

Human development is regulated by intricate, and interconnected, signal transduction networks. Given the complexity, deciphering the effects of mutations that give rise to abnormal development can be challenging. Using Drosophila melanogaster can simplify the puzzle of studying human disorders as flies have little genetic redundancy and are significantly easier, cheaper, and faster to raise than other vertebrate models. I use Drosophila to characterize Dishevelled1 (DVL1) mutations obtained from patients with Robinow Syndrome (RS). RS is a rare genetic disorder associated craniofacial abnormalities and shortened stature. Most of the mutations associated with RS affect components of the non-canonical/Planar Cell Polarity (PCP) pathway of Wnt signaling. Wnt signaling is involved in embryonic development and homeostasis. The two main pathways, canonical and non-canonical/PCP Wnt signaling, require DVL but there is still much to learn about PCP signaling which mediates cytoskeletal rearrangement events and orients cell polarity within the epithelial plane. There are 3 DVL proteins found in vertebrates, and a single ortholog, Dsh, in Drosophila. Each of the DVL1 variants I study have unique frameshift mutations that replace the highly conserved C-terminus with the same novel peptide sequence of no known homology. I use the Gal4-UAS system to express wildtype human DVL1 and three DVL1 variants in Drosophila. My research has shown that these DVL1 patient variants disrupt the stability of Armadillo/β-catenin, ectopically induce PCP/JNK signaling and activate apoptosis. Furthermore, the variants induce several novel phenotypes in wing tissue such as anterior cross vein abnormalities, ectopic bristles, and vein thickening, suggesting novel functions in other conserved signaling pathways. By understanding how conserved signaling pathways are altered by these DVL1 variants, we gain insight into the underlying mechanisms of non-canonical Wnt signaling and more broadly, how development in individuals with RS is altered. This information may guide future therapeutics for RS patients.

Characterizing Robinow Syndrome-associated DVL1 mutations in Drosophila