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We identified Dvl as a NEK2 substrate and described that they mediate disassembling of centrosomal linker proteins from the centrosome, a process essential for duplicating the centrioles and polarization of the mitotic spindle during mitosis.Such findings are of tremendous importance in cancer research and in the context of ciliopathies which show defects in the centrosomal structures.Analysis of Wnt5a-/-, Wnt5a overexpressing, Wnt5a-/-; Ror2-/- and Ror2-/-; Vangl2-/- mice identified a function of the Wnt5a-Ror2/Vangl2 signaling axis in the VM morphogenesis and in m DA neuron development.
In study V, we investigated whether Leucine-rich repeat kinase 2 (Lrrk2), the protein product of the park8 gene, which is mutated in more than 40% of patients with inherited PD, can interact with the Wnt/PCP pathway by using a proteomic screening.
We describe that Lrrk2 interacts with a number of Wnt/PCP components in dopaminergic cells, in the VM of E18.5 mice embryos, and in a human cell line.
Moreover, we suggest that the pathogenesis of PD may involve an alteration in the balance between these two Wnt signaling pathways. Cervenka I, Valnohova J, Bernatik O, Harnos J, Radsetoulal M, Sedova K, Hanakova K, Potesil D, Sedlackova M, Salasova A, Steinhart Z, Angers S, Schulte G, Hampl A, Zdrahal Z, Bryja V. Fulltext (DOI) Pubmed View record in Web of Science® II.
Dishevelled is a NEK2 kinase substrate controlling dynamics of centrosomal linker proteins. Kaiser K, Gyllborg D, Salašová A, Molina FL, Laguna-Goya R, Potěšil D, Barker RA, Gato Casado Á, Bryja V, Arenas E, Villaescusa JC: WNT5A is transported via lipoprotein particles in the cerebrospinal fluid and regulates progenitor proliferation. Gyllborg D, Salašová A, Toledo EM, Gao B, Yang Y, Villaescusa JC, van Amerongen R, Arenas E: Ror2 and Vangl2 control dopaminergic neurogenesis and multiple aspects of cell polarity in the midbrain floor plate. Salašová A, Yokota C, Kasper Kjaer-Sorensen, Vestergaard B, Navis A, Thomasen P, Bernatik O, Varas M, Ernfors P, Bryja V, Nykjaer A, Arenas E: Proneurotrophin receptor Sor CS2 is a novel regulator of WNT/PCP pathway during embryogenesis. Salašová A, Yokota C, Potěšil D, Zdráhal Z, Bryja V, Arenas E.
Moreover, we found a novel phenotype of bilateral asymmetry in Ror2-/-; Vangl2-/- animals which suggests that Vangl2 alone or in a complex with Ror2 controls the correct position, proliferation and differentiation of m DA progenitors into m DA neuroblasts and neurons.
Our results additionally identify a novel role of Wnt/PCP signaling in controlling m DA neurogenesis, which may be of interest for the development of novel regenerative approaches to treat neurodegenerative diseases which affect m DA neurons, such as Parkinson's disease.
Particularly, we show the capacity of Lrrk2 to inhibit Wnt/β-catenin signaling in vitro and in vivo in X. We observed that these regulatory changes depend on the presence of Prickle1 and Dvl.
Our results thus provide novel insights into the molecular mechanisms by which Lrrk2 and Wnt signaling interact, and describe Lrrk2 and Prickle1 as novel dual regulators of Wnt/PCP and Wnt/β-catenin signaling.
We further describe that secreted Wnt5a forms a complex with high-density lipoprotein particles containing Apo E and Apo J, but is not found in exosomes.
Analysis of the Wnt5a deficient mice revealed a possible function of Wnt5a in the choroid plexus to inhibit progenitor proliferation in the neighbor ventricular zone.