Abstract
Background: The Wnt gene family encode secreted glucoproteins that function in intercellular signalling. They play essential roles in shaping the nervous system during embryonic development. The Wnts signal via at least 3 different pathways. These include the b-catenin, the planar cell polarity (PCP) and the calcium pathways. Wnt signalling can inhibit the cells continous degradation of b-catenin degradation, thus allowing â-catenin to translocate to the nucleus were it in association with transcription factors cause target gene transcription. â-catenin is also associated with adherens junctions, were it acts as an anchor for cadherins involved in cell-cell contacts, and for actin microfibers of the cytoskeleton. The planar cell polarity and the calcium pathways are believed to be important regulators of gastrulation and neurulation in vertebrates.
Methods: Fertilized mouse oocytes were injected with a gene construct which utilize the nestin gene to direct expression of Wnt7a to neural stem cells. The treated oocytes were implanted into pseudopregnant females and allowed to develop for 7,5–14,5 days. The embryos were then genotyped by PCR, cryosectioned and studied by standard histochemichal methods.
Results: Embryos overexpressing Wnt7a displayed aberrant morphologies that seemed to be related to a defective neurulation. Surprisingly, the transgenic embryos partly phenocopied mouse embryos that had been let to develop in the presence of cytochalasin, a substance that disrupts actin microfilaments. â-catenin immunofluorescence was reduced over adherence junctions of transgenic embryos. Double labelling with phalloidin revealed an overlapping reduction in actin microfilaments. Expression of a gene essential for the PCP pathway, Vangl2, was upregulated in the transgenic embryos.
Conclusion: The increased Vangl2 expression indicate that Wnt7a can activate the PCP pathway in mammals. This in itself can lead to an impaired neurulation by affecting cell migration. However, part of the phenotype observed in the transgenics was likely due to the reduced levels of â-catenin and actin microfilaments at the adherens junctions. This could either be an effect of the PCP and the â-catenin pathway counteracting each other, or since the PCP gene Scribble binds to adherens junctions in Drosophila, by a direct effect of PCP signaling on adherens junctions. This demonstrates that a Wnt ligand can be bioactive also by affecting â-catenins function as a part of the cytoskeleton.
Article PDF
Author information
Authors and Affiliations
Rights and permissions
About this article
Cite this article
Shariatmadari, M., Peyronnet, J., Papachristou, P. et al. 226 Overexpression of Wnt7a in Transgenic Mouse Neural Stem Cells Increase Vangl2 Expression and Impair Neurulation by Disturbing Actin Microfilament Formation. Pediatr Res 56, 502 (2004). https://doi.org/10.1203/00006450-200409000-00249
Issue Date:
DOI: https://doi.org/10.1203/00006450-200409000-00249