Browsing by Author "Oliva, Carlos "

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    An Early Disturbance in Serotonergic Neurotransmission Contributes to the Onset of Parkinsonian Phenotypes in Drosophila melanogaster
    (MDPI, 2022) Zárate Canales, Rafaella Victoria; Hidalgo, Sergio; Navarro, Nicole; Molina Mateo, Daniela Francisca; Arancibia, Duxan; Rojo Cortés, Francisca Rayén; Oliva, Carlos; Andrés Coke, María Estela; Zamorano, Pedro; Campusano Astorga, Jorge Mauricio
    Parkinson's disease (PD) is a neurodegenerative disease characterized by motor symptoms and dopaminergic cell loss. A pre-symptomatic phase characterized by non-motor symptoms precedes the onset of motor alterations. Two recent PET studies in human carriers of mutations associated with familial PD demonstrate an early serotonergic commitment-alteration in SERT binding-before any dopaminergic or motor dysfunction, that is, at putative PD pre-symptomatic stages. These findings support the hypothesis that early alterations in the serotonergic system could contribute to the progression of PD, an idea difficult to be tested in humans. Here, we study some components of the serotonergic system during the pre-symptomatic phase in a well-characterized Drosophila PD model, Pink1(B9) mutant flies. We detected lower brain serotonin content in Pink1(B9) flies, accompanied by reduced activity of SERT before the onset of motor dysfunctions. We also explored the consequences of a brief early manipulation of the serotonergic system in the development of motor symptoms later in aged animals. Feeding young Pink1(B9) flies with fluoxetine, a SERT blocker, prevents the loss of dopaminergic neurons and ameliorates motor impairment observed in aged mutant flies. Surprisingly, the same pharmacological manipulation in young control flies results in aged animals exhibiting a PD-like phenotype. Our findings support that an early dysfunction in the serotonergic system precedes and contributes to the onset of the Parkinsonian phenotype in Drosophila.
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    Autocrine/Paracrine Slit-Robo Signaling Controls Optic Lobe Development in Drosophila melanogaster
    (2022) Gonzalez-Ramirez, M. Constanza; Rojo-Cortes, Francisca; Candia, Noemi; Garay-Montecinos, Jorge; Guzman-Palma, Pablo; Campusano, Jorge M. M.; Oliva, Carlos
    Cell segregation mechanisms play essential roles during the development of the central nervous system (CNS) to support its organization into distinct compartments. The Slit protein is a secreted signal, classically considered a paracrine repellent for axonal growth through Robo receptors. However, its function in the compartmentalization of CNS is less explored. In this work, we show that Slit and Robo3 are expressed in the same neuronal population of the Drosophila optic lobe, where they are required for the correct compartmentalization of optic lobe neuropils by the action of an autocrine/paracrine mechanism. We characterize the endocytic route followed by the Slit/Robo3 complex and detected genetic interactions with genes involved in endocytosis and actin dynamics. Thus, we report that the Slit-Robo3 pathway regulates the morphogenesis of the optic lobe through an atypical autocrine/paracrine mechanism in addition to its role in axon guidance, and in association with proteins of the endocytic pathway and small GTPases.
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    Bioinformatic analysis predicts that ethanol exposure during early development causes alternative splicing alterations of genes involved in RNA post-transcriptional regulation
    (2023) Fuentes-Beals, Camilo; Olivares-Costa, Montserrat; Andres, Maria Estela; Haeger, Paola A.; Riadi, Gonzalo; Oliva, Carlos; Faunes, Fernando
    Prenatal ethanol exposure is associated with neurodevelopmental defects and long-lasting cognitive deficits, which are grouped as fetal alcohol spectrum disorders (FASD). The molecular mechanisms underlying FASD are incompletely characterized. Alternative splicing, including the insertion of microexons (exons of less than 30 nucleotides in length), is highly prevalent in the nervous system. However, whether ethanol exposure can have acute or chronic deleterious effects in this process is poorly understood. In this work, we used the bioinformatic tools VAST-TOOLS, rMATS, MAJIQ, and MicroExonator to predict alternative splicing events affected by ethanol from available RNA sequencing data. Experimental protocols of ethanol exposure included human cortical tissue development, human embryoid body differentiation, and mouse development. We found common genes with predicted differential alternative splicing using distinct bioinformatic tools in different experimental designs. Notably, Gene Ontology and KEGG analysis revealed that the alternative splicing of genes related to RNA processing and protein synthesis was commonly affected in the different ethanol exposure schemes. In addition, the inclusion of microexons was also affected by ethanol. This bioinformatic analysis provides a reliable list of candidate genes whose splicing is affected by ethanol during nervous system development. Furthermore, our results suggest that ethanol particularly modifies the alternative splicing of genes related to post-transcriptional regulation, which probably affects neuronal proteome complexity and brain function.
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    Cell segregation and boundary formation during nervous system development
    (2021) Constanza Gonzalez-Ramirez, M.; Guzman-Palma, Pablo; Oliva, Carlos
    The development of multicellular organisms involves three main events: differentiation, growth, and morphogenesis. These processes need to be coordinated for a correct developmental program to work. Mechanisms of cell segregation and the formation of boundaries during development play essential roles in this coordination, allowing the generation and maintenance of distinct regions in an organism.These mechanisms are also at work in the nervous system. The process of regionalization involves first the patterning of the developing organism through gradients and the expression of transcription factors in specific regions. Once different tissues have been induced, segregation mechanisms may operate to avoid cell mixing between different compartments.Three mechanisms have been proposed to achieve segregation: (1) differential affinity, which mainly involves the expression of distinct pools of adhesion molecules such as members of the cadherin superfamily; (2) contact inhibition, which is largely mediated by Eph-ephrin signaling; and (3) cortical tension, which involves the actomyosin cytoskeleton. In many instances, these mechanisms collaborate in cell segregation. In the last three decades, there have been several advances in our understanding of how cell segregation and boundaries participate in the development of the nervous system. Interestingly, as in other aspects of development, the molecular players are remarkably similar between vertebrates and invertebrates. Here we summarize the main concepts of cell segregation and boundary formation, focusing on the nervous system and highlighting the similarities between vertebrate and invertebrate model organisms.
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    Dlg Is Required for Short-Term Memory and Interacts with NMDAR in the Drosophila Brain
    (2022) Bertin, Francisca; Moya-Alvarado, Guillermo; Quiroz-Manriquez, Eduardo; Ibacache, Andres; Kohler-Solis, Andres; Oliva, Carlos; Sierralta, Jimena
    The vertebrates' scaffold proteins of the Dlg-MAGUK family are involved in the recruitment, clustering, and anchoring of glutamate receptors to the postsynaptic density, particularly the NMDA subtype glutamate-receptors (NRs), necessary for long-term memory and LTP. In Drosophila, the only gene of the subfamily generates two main products, dlgA, broadly expressed, and dlgS97, restricted to the nervous system. In the Drosophila brain, NRs are expressed in the adult brain and are involved in memory, however, the role of Dlg in these processes and its relationship with NRs has been scarcely explored. Here, we show that the dlg mutants display defects in short-term memory in the olfactory associative-learning paradigm. These defects are dependent on the presence of DlgS97 in the Mushroom Body (MB) synapses. Moreover, Dlg is immunoprecipitated with NRs in the adult brain. Dlg is also expressed in the larval neuromuscular junction (NMJ) pre and post-synaptically and is important for development and synaptic function, however, NR is absent in this synapse. Despite that, we found changes in the short-term plasticity paradigms in dlg mutant larval NMJ. Together our results show that larval NMJ and the adult brain relies on Dlg for short-term memory/plasticity, but the mechanisms differ in the two types of synapses.
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    Early-life nutrition interacts with developmental genes to shape the brain and sleep behavior in Drosophila melanogaster
    (2023) Olivares, Gonzalo H.; Nunez-Villegas, Franco; Candia, Noemi; Orostica, Karen; Gonzalez-Ramirez, M. Constanza; Vega-Macaya, Franco; Zuniga, Nolberto; Molina, Cristian; Oliva, Carlos; Mackay, Trudy F. C.; Verdugo, Ricardo A.; Olguin, Patricio
    The mechanisms by which the genotype interacts with nutrition during development to contribute to the variation of complex behaviors and brain morphology of adults are not well understood. Here we use the Drosophila Genetic Reference Panel to identify genes and pathways underlying these interactions in sleep behavior and mushroom body morphology. We show that early-life nutritional restriction effects on sleep behavior and brain morphology depends on the genotype. We mapped genes associated with sleep sensitivity to early-life nutrition, which were enriched for protein-protein interactions responsible for translation, endocytosis regulation, ubiquitination, lipid metabolism, and neural development. By manipulating the expression of candidate genes in the mushroom bodies (MBs) and all neurons, we confirm that genes regulating neural development, translation and insulin signaling contribute to the variable response of sleep and brain morphology to early-life nutrition. We show that the interaction between differential expression of candidate genes with nutritional restriction in early life resides in the MBs or other neurons and that these effects are sex-specific. Natural variations in genes that control the systemic response to nutrition and brain development and function interact with early-life nutrition in different types of neurons to contribute to the variation of brain morphology and adult sleep behavior.
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    Lipophorin receptors regulate mushroom bodies development and participate in learning, memory, and sleep in flies
    (2021) Rojo-Cortes, Francisca ; Tapia-Valladares, Victoria ; Fuenzalida-Uribe, Nicolas ; Hidalgo, Sergio ; Roa, Candy B. ; Gonzalez-Ramirez, Maria-Constanza ; Oliva, Carlos ; Campusano, Jorge M. ; Marzolo, Maria-Paz
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    The transcription factor SoxD controls neuronal guidance in the Drosophila visual system
    (2018) Contreras, Esteban G. ; Palominos, Tomás ; Glavic, Álvaro ; Brand, Andrea H. ; Sierralta, Jimena ; Oliva, Carlos