Browsing by Author "Colombres Raby, Marcela"

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    Genome wide identification of new Wnt/β-catenin target genes in the human genome using CART method
    (BioMed Central Ltd., 2010) Hodar, Christian; Assar, Rodrigo; Colombres Raby, Marcela; Aravena, Andrés; Pavez, Leonardo; Gonzalez, Mauricio; Martínez, Servet; Inestrosa, Nibaldo C.; Maass, Alejandro
    Background: The importance of in silico predictions for understanding cellular processes is now widely accepted, and a variety of algorithms useful for studying different biological features have been designed. In particular, the prediction of cis regulatory modules in non-coding human genome regions represents a major challenge for understanding gene regulation in several diseases. Recently, studies of the Wnt signaling pathway revealed a connection with neurodegenerative diseases such as Alzheimer's. In this article, we construct a classification tool that uses the transcription factor binding site motifs composition of some gene promoters to identify new Wnt/beta-catenin pathway target genes potentially involved in brain diseases. Results: In this study, we propose 89 new Wnt/beta-catenin pathway target genes predicted in silico by using a method based on multiple Classification and Regression Tree (CART) analysis. We used as decision variables the presence of transcription factor binding site motifs in the upstream region of each gene. This prediction was validated by RT-qPCR in a sample of 9 genes. As expected, LEF1, a member of the T-cell factor/lymphoid enhancer-binding factor family (TCF/LEF1), was relevant for the classification algorithm and, remarkably, other factors related directly or indirectly to the inflammatory response and amyloidogenic processes also appeared to be relevant for the classification. Among the 89 new Wnt/beta-catenin pathway targets, we found a group expressed in brain tissue that could be involved in diverse responses to neurodegenerative diseases, like Alzheimer's disease (AD). These genes represent new candidates to protect cells against amyloid beta toxicity, in agreement with the proposed neuroprotective role of the Wnt signaling pathway. Conclusions: Our multiple CART strategy proved to be an effective tool to identify new Wnt/beta-catenin pathway targets based on the study of their regulatory regions in the human genome. In particular, several of these genes represent a new group of transcriptional dependent targets of the canonical Wnt pathway. The functions of these genes indicate that they are involved in pathophysiology related to Alzheimer's disease or other brain disorders.
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    Wnt signaling in neuroprotection and stem cell differentiation
    (2008) Toledo Maldonado, Enrique Daniel; Colombres Raby, Marcela; Inestrosa Cantín, Nibaldo
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    β-amyloid oligomers affect the structure and function of the postsynaptic region: Role of the Wnt signaling pathway
    (2008) Dinamarca Ceballos, Margarita Constanza; Colombres Raby, Marcela; Cerpa Nebott ,Waldo Francisco; Bonansco, Christian; Inestrosa Cantín, Nibaldo
    Background: Alzheimer's disease (AD) is the most prevalent neurodegenerative disease in the growing population of elderly people. Synaptic dysfunction is an early manifestation of AD. The cellular mechanism by which β-amyloid peptide (Aβ) affects synapses remains unclear. Aβ oligomers target synapses in cultured rat hippocampal neurons suggesting that they play a key role in the regulation of synapses. Objective: The aim of this work is to study the effect of Aβ oligomers on the central synapses and the possible role of the Wnt signaling pathway in preventing the Aβ effects. Methods: We used rat hippocampal neurons, immunofluorescence and western blot procedures to detect synaptic proteins. Results: Aβ oligomers induced a reduction of the postsynaptic density protein 95 (PSD-95) and the NMDA glutamate receptors. We found that Wnt-5a, a noncanonical Wnt ligand, prevents the decrease triggered by Aβ oligomers in the glutamate receptor and PSD-95. Conclusion: Altogether, our results suggest that Aβ oligomers decrease the synaptic responses by affecting the postsynaptic region at different levels. The Wnt signaling activation prevents synaptic damage induced by Aβ, which raises the possibility of a new therapeutic intervention for the treatment of synaptic changes observed in AD. Copyright © 2008 S. Karger AG.