Robinow Syndrome DVL1 variants disrupt morphogenesis and appendage formation in a Drosophila disease model

Abstract

Robinow Syndrome is a rare developmental syndrome caused by variants in numerous genes involved in Wnt signaling pathways. We previously showed that expression of patient variants in Drosophila and a chicken model disrupts the balance of canonical and non-canonical/PCP Wnt signaling. We also noted neomorphic effects that warranted further investigation. In this study, we examine morphological changes that occur as a result of one variant, DVL11519{Delta}T, that serves as a prototype for the other pathogenic variants. We show that epithelial imaginal disc development is disrupted in legs and wings. Shortened leg segments are reminiscent of shortened limb bones seen in RS patients. We find that imaginal disc development is disrupted and accompanied by increased cell death, without changes in cell proliferation. Furthermore, we find altered dynamics of basement membrane components and modulators. Notably we find increased MMP1 expression and tissue distortion, which is dependent on JNK signaling. We also find enhanced collagen IV (Viking) secreted from cells expressing DVL11519{Delta}T. Through these studies we have gained more insight into developmental consequences of DVL1 variants implicated in autosomal dominant Robinow Syndrome.