Developmental dynamics : an official publication of the American Association of Anatomists · 2025
Robinow syndrome DVL1 variants disrupt morphogenesis and appendage formation in a Drosophila disease model.
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Akarsu Gamze, MacCharles Katja R, Wong Kenneth Kin Lam, Richman Joy M, Verheyen Esther M
Аннотация
BACKGROUND: Robinow syndrome is a rare developmental syndrome caused by variants in genes in Wnt signaling pathways. We previously showed that expression of patient variants in Dishevelled 1 (DVL1) in Drosophila and chicken models disrupts the balance of canonical and non-canonical Wnt signaling.
RESULTS: In this study, we further examine morphological changes that occur due to expression of DVL11519ΔT, which serves as a prototype for other pathogenic variants. We show that epithelial imaginal disc development is disrupted in legs and wings and accompanied by increased cell death, without changes in cell proliferation. By inhibiting caspase-dependent cell death, we show that the altered epithelial morphology is not solely due to variant-induced cell death. Furthermore, we find alterations of basement membrane components and modulators. Notably we find ectopic Mmp1 expression and tissue distortion, which is dependent on JNK signaling. We also find an abnormal abundance of Drosophila collagen IV (Viking) in pupal wing development. Due to the complex nature of appendage development, we also examined the Bone Morphogenetic Protein pathway and found elevated signaling activity via the transcriptional readout dad-lacZ.
CONCLUSIONS: Through these studies, we have gained more insight into the developmental consequences of DVL1 variants implicated in autosomal dominant Robinow syndrome.
RESULTS: In this study, we further examine morphological changes that occur due to expression of DVL11519ΔT, which serves as a prototype for other pathogenic variants. We show that epithelial imaginal disc development is disrupted in legs and wings and accompanied by increased cell death, without changes in cell proliferation. By inhibiting caspase-dependent cell death, we show that the altered epithelial morphology is not solely due to variant-induced cell death. Furthermore, we find alterations of basement membrane components and modulators. Notably we find ectopic Mmp1 expression and tissue distortion, which is dependent on JNK signaling. We also find an abnormal abundance of Drosophila collagen IV (Viking) in pupal wing development. Due to the complex nature of appendage development, we also examined the Bone Morphogenetic Protein pathway and found elevated signaling activity via the transcriptional readout dad-lacZ.
CONCLUSIONS: Through these studies, we have gained more insight into the developmental consequences of DVL1 variants implicated in autosomal dominant Robinow syndrome.