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Published on: April 11, 2011
Robinow syndrome DVL1 variants disrupt morphogenesis and appendage formation in a Drosophila disease model
Gamze Akarsu1,2, Katja R MacCharles1,2, Kenneth Kin Lam Wong1,2
1Department of Molecular Biology and Biochemistry, Simon Fraser University, Burnaby, British Columbia, Canada.
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.
Insights
Robinow syndrome variants in Dishevelled 1 (DVL1) disrupt epithelial development by altering cell death and basement membranes. This research provides insights into the developmental consequences of these genetic mutations.
Area of Science:
- Developmental Biology
- Genetics
- Molecular Biology
Background:
- Robinow syndrome is a rare developmental disorder linked to Wnt signaling pathway gene variants.
- Previous studies demonstrated that Dishevelled 1 (DVL1) variants disrupt Wnt signaling balance in model organisms.
Purpose of the Study:
- To investigate the morphological consequences of expressing a prototype DVL1 pathogenic variant (DVL11519ΔT).
- To elucidate the role of cell death, basement membrane integrity, and signaling pathways in DVL1 variant-induced developmental defects.
Main Methods:
- Expression of DVL11519ΔT in Drosophila models.
- Analysis of epithelial imaginal disc development, cell proliferation, and apoptosis.
- Assessment of basement membrane components, matrix metalloproteinase activity (Mmp1), JNK signaling, collagen IV (Viking) abundance, and Bone Morphogenetic Protein (BMP) pathway activity (dad-lacZ).
Main Results:
- DVL11519ΔT expression disrupted leg and wing epithelial imaginal disc development, increasing cell death without affecting proliferation.
- Altered epithelial morphology was not solely due to caspase-dependent cell death.
- Observed were changes in basement membrane components, ectopic Mmp1 expression, tissue distortion dependent on JNK signaling, abnormal collagen IV abundance, and elevated BMP signaling.
Conclusions:
- DVL1 variants implicated in autosomal dominant Robinow syndrome cause significant developmental defects.
- These findings enhance understanding of the complex developmental consequences of DVL1 variants in Robinow syndrome.
