Role Of Wnt Signaling And Gsk3 In Development

The development of animal organs requires a coordination of cell proliferation and morphogenesis processes. Wnt proteins have been described to regulate early events in the developing nervous system. Wnt3, -3a, -7b, and -8b participate in the development of the forebrain, a region that gives rise to the hippocampus. Ablation of Wntl results in severe defects of the midbrain, the cerebellum and the developing spinal cord, while ablation of Wnt3a results in a total loss of the hippocampus. The deletion of the Wntl gene also results in loss of the midbrain-hindbrain junction and the consequent loss of dopaminergic (DA) neurons [4]. In fact Wnts are involved in the acquisition of a DA phenotype in the developing ventral mesencephalon. Wnt1 mainly regulates the proliferation of neural precursors while Wnt5a is involved in the conversion of precursors positive for nuclear receptor-related factor 1 into DA neurons. Wnts are palmitoylated glycoproteins, poorly soluble ligands, prop erty that limitis their potential use in a clinical set up. One proposed way to bypass this limitation could be the development and application of drugs that modulate Wnt signaling pathways. In this aspect, chemical inhibitors of GSK-3P, indirubin-3-monoxime and kenpaullone, were found to increase neuronal differentiation in ventral mesencephalon precursor cultures [5]. In addition the GSK-3P-specific inhibitor kenpaullone increased the size of the DA neuron population tyrosine hydroxylase positive neurons, mimicking an effect of Wnt's. Furthermore it was shown that GSK-3P inhibitors stabilized P-catenin in ventral mesencephalic precursors resulting in increased DA differentiation. These compounds have been suggested to be used in the improvement of stem cell therapy approaches in neurodegenerative diseases.

In Drosophila the Wingless signaling pathway controls the formation of the antero-posterior boundary of the Imaginal discs, and the homologous Wnt pathways in vertebrates are essential for development of many organs [6]. These pathways also control cell proliferation in respective target tissues. In Drosophila the Wingless pathway requires armadillo (homologue of P-catenin), while the GSK-3 homologue shaggy (also known as zeste-white 3) negatively regulates the pathway and thus proliferation of the target cells. In fact Drosophila shaggy plays a critical role during Drosophila neurogenesis. The ectopic expression of Wingless leads to induction of ectopic structures and general overproliferation of the surrounding cells [7]. Interestingly, Wnt1 (a Wg homologue in mice) has been implicated in development of vertebrate brain [4].

During Xenopus embryonic development GSK-3 acts as a negative regulator of dorsal axis formation [8]. Inhibition of GSK-3 activity leads to stabilization of P-catenin and expression of target dorsalizing genes [9,10]. GSK-3 promotes P-catenin phosphorylation, which stimulates its degradation by the ubiquitin-proteasome system [11]. Maternally expressed P-catenin is essential for dorsal determination and is localized to the future dorsal side of the embryo just after egg fertilization [12,13]. Thus meiotic maturation can be considered as a preparation for asymmetric localization of P-catenin and dorsal axis formation. Interestingly insulin, as well as progesterone, can promote meiotic maturation of Xenopus oocytes.

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