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These include control of proliferation, differentiation, migration and cell fate decisions.Deregulation of Wnt/PCP signaling can lead to many developmental abnormalities and cancer.
To better understand the functional complexity of the Wnt/PCP signaling, we examined a number of transgenic mice models, which allowed us to uncover the function of Wnt/PCP protein complexes in the mammalian CNS.
Finally, some of our observations were confirmed by using human prenatal brain tissue (study II).
These produce signals that influence the fate, histogenic organisation and growth of adjacent tissues, resulting in spatial patterning.
Members of the Wnt gene family are among few secreted proteins expressed in patterning centers of the developing CNS, such as the pallial-subpallial boundary (PSB) and the cortical hem.
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 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.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.Our study shows that correct Wnt5a expression levels are crucial for VM morphogenesis, m DA neurogenesis and m DA neuron maturation.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.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.These data reveal that the two pathways previously considered to be independent, Wnt/PCP and proneurotrophin receptor signaling, functionally interact.Moreover, our results identify Sor CS2 as a novel regulator of Wnt/PCP signaling in vertebral embryogenesis.