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BACKGROUND: Drosophila melanogaster lipophorin receptors (LpRs), LpR1 and LpR2, are members of the LDLR family known to mediate lipid uptake in a range of organisms from Drosophila to humans. The vertebrate orthologs of LpRs, ApoER2 and VLDL-R, function as receptors of a glycoprotein involved in development of the central nervous system, Reelin, which is not present in flies. ApoER2 and VLDL-R are associated with the development and function of the hippocampus and cerebral cortex, important association areas in the mammalian brain, as well as with neurodevelopmental and neurodegenerative disorders linked to those regions. It is currently unknown whether LpRs play similar roles in the Drosophila brain. RESULTS: We report that LpR-deficient flies exhibit impaired olfactory memory and sleep patterns, which seem to reflect anatomical defects found in a critical brain association area, the mushroom bodies (MB). Moreover, cultured MB neurons respond to mammalian Reelin by increasing the complexity of their neurite arborization. This effect depends on LpRs and Dab, the Drosophila ortholog of the Reelin signaling adaptor protein Dab1. In vitro, two of the long isoforms of LpRs allow the internalization of Reelin, suggesting that Drosophila LpRs interact with human Reelin to induce downstream cellular events. CONCLUSIONS: These findings demonstrate that LpRs contribute to MB development and function, supporting the existence of a LpR-dependent signaling in Drosophila, and advance our understanding of the molecular factors functioning in neural systems to generate complex behaviors in this model. Our results further emphasize the importance of Drosophila as a model to investigate the alterations in specific genes contributing to neural disorders.
Assuntos
Proteínas de Drosophila , Drosophila melanogaster , Corpos Pedunculados , Receptores Citoplasmáticos e Nucleares , Animais , Moléculas de Adesão Celular Neuronais/genética , Moléculas de Adesão Celular Neuronais/metabolismo , Proteínas de Drosophila/genética , Proteínas de Drosophila/metabolismo , Drosophila melanogaster/genética , Drosophila melanogaster/metabolismo , Proteínas da Matriz Extracelular/genética , Proteínas da Matriz Extracelular/metabolismo , Proteínas da Matriz Extracelular/farmacologia , Corpos Pedunculados/metabolismo , Proteínas do Tecido Nervoso/genética , Proteínas do Tecido Nervoso/metabolismo , Receptores Citoplasmáticos e Nucleares/metabolismo , Proteína Reelina , Serina Endopeptidases/metabolismoRESUMO
Neurons are highly polarized cells requiring precise regulation of trafficking and targeting of membrane proteins to generate and maintain different and specialized compartments, such as axons and dendrites. Disruption of the Golgi apparatus (GA) secretory pathway in developing neurons alters axon/dendritic formation. Therefore, detailed knowledge of the mechanisms underlying vesicles exiting from the GA is crucial for understanding neuronal polarity. In this study, we analyzed the role of Brefeldin A-Ribosylated Substrate (CtBP1-S/BARS), a member of the C-terminal-binding protein family, in the regulation of neuronal morphological polarization and the exit of membrane proteins from the Trans Golgi Network. Here, we show that BARS is expressed during neuronal development in vitro and that RNAi suppression of BARS inhibits axonal and dendritic elongation in hippocampal neuronal cultures as well as largely perturbed neuronal migration and multipolar-to-bipolar transition during cortical development in situ. In addition, using plasma membrane (PM) proteins fused to GFP and engineered with reversible aggregation domains, we observed that expression of fission dominant-negative BARS delays the exit of dendritic and axonal membrane protein-containing carriers from the GA. Taken together, these data provide the first set of evidence suggesting a role for BARS in neuronal development by regulating post-Golgi membrane trafficking.
Assuntos
Complexo de Golgi , Neurônios , Axônios/metabolismo , Complexo de Golgi/metabolismo , Proteínas de Membrana/metabolismo , Neurônios/fisiologia , Rede trans-Golgi/metabolismoRESUMO
Maternal malnutrition remains one of the major adversities affecting brain development and long-term mental health outcomes, increasing the risk to develop anxiety and depressive disorders. We have previously shown that malnutrition-induced anxiety-like behaviours can be rescued by a social and sensory stimulation (enriched environment) in male mice. Here, we expand these findings to adult female mice and profiled genome-wide ventral hippocampal 5hmC levels related to malnutrition-induced anxiety-like behaviours and their rescue by an enriched environment. This approach revealed 508 differentially hydroxymethylated genes associated with protein malnutrition and that several genes (N = 34) exhibited a restored 5hmC abundance to control levels following exposure to an enriched environment, including genes involved in neuronal functions like dendrite outgrowth, axon guidance, and maintenance of neuronal circuits (e.g. Fltr3, Itsn1, Lman1, Lsamp, Nav, and Ror1) and epigenetic mechanisms (e.g. Hdac9 and Dicer1). Sequence motif predictions indicated that 5hmC may be modulating the binding of transcription factors for several of these transcripts, suggesting a regulatory role for 5hmC in response to perinatal malnutrition and exposure to an enriched environment. Together, these findings establish a role for 5hmC in early-life malnutrition and reveal genes linked to malnutrition-induced anxious behaviours that are mitigated by an enriched environment.
Assuntos
Metilação de DNA , Desnutrição , 5-Metilcitosina/análogos & derivados , Animais , Epigênese Genética , Feminino , Masculino , CamundongosRESUMO
Emerging evidence shows that Rab11 recycling endosomes (REs Rab11) are essential for several neuronal processes, including the proper functioning of growth cones, synapse architecture regulation and neuronal migration. However, several aspects of REs Rab11 remain unclear, such as its sub-cellular distribution across neuronal development, contribution to dendritic tree organization and its consequences in memory formation. In this work we show a spatio-temporal correlation between the endogenous localization of REs Rab11 and developmental stage of neurons. Furthermore, Rab11-suppressed neurons showed an increase on dendritic branching (without altering total dendritic length) and misdistribution of dendritic proteins in cultured neurons. In addition, suppression of Rab11 in adult rat brains in vivo (by expressing shRab11 through lentiviral infection), showed a decrease on both the sensitivity to induce long-term potentiation and hippocampal-dependent memory acquisition. Taken together, our results suggest that REs Rab11 expression is required for a proper dendritic architecture and branching, controlling key aspects of synaptic plasticity and spatial memory formation.
Assuntos
Dendritos/metabolismo , Plasticidade Neuronal , Neurônios/fisiologia , Memória Espacial , Proteínas rab de Ligação ao GTP/genética , Animais , Giro Denteado/fisiologia , Fenômenos Eletrofisiológicos , Feminino , Hipocampo/fisiologia , Potenciação de Longa Duração , Masculino , Gravidez , Ratos , Proteínas rab de Ligação ao GTP/metabolismoRESUMO
Endocytic recycling is an intracellular process that returns internalized molecules back to the plasma membrane and plays crucial roles not only in the reuse of receptor molecules but also in the remodeling of the different components of this membrane. This process is required for a diversity of cellular events, including neuronal morphology acquisition and functional regulation, among others. The recycling endosome (RE) is a key vesicular component involved in endocytic recycling. Recycling back to the cell surface may occur with the participation of several different Rab proteins, which are master regulators of membrane/protein trafficking in nerve cells. The RE consists of a network of interconnected and functionally distinct tubular subdomains that originate from sorting endosomes and transport their cargoes along microtubule tracks, by fast or slow recycling pathways. Different populations of REs, particularly those formed by Rab11, Rab35, and Arf6, are associated with a myriad of signaling proteins. In this review, we discuss the cumulative evidence suggesting the existence of heterogeneous domains of REs, controlling different aspects of neurogenesis, with a particular focus on the commonalities and singularities of these REs and their contribution to nerve development and differentiation in several animal models.
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Teneurins (Tens) are a highly conserved family of proteins necessary for cell-cell adhesion. Tens can be cleaved, and some of their proteolytic products, such as the teneurin c-terminal associated-peptide (TCAP) and the intracellular domain (ICD), have been demonstrated to be biologically active. Although Tens are considered critical for central nervous system development, they have also been demonstrated to play important roles in adult tissues, suggesting a potential link between their deregulation and various pathological processes, including neurodegeneration and cancer. However, knowledge regarding how Ten expression is modulated is almost absent. Relevantly, the functions of Tens resemble several of the effects of canonical and non-canonical Wnt pathway activation, including the effects of the Wnt pathways on neuronal development and function as well as their pivotal roles during carcinogenesis. Accordingly, in this initial study, we decided to evaluate whether Wnt signaling can modulate the expression of Tens. Remarkably, in the present work, we used a specific inhibitor of porcupine, the key enzyme for Wnt ligand secretion, to not only demonstrate the involvement of Wnt signaling in regulating Ten-3 expression for the first time but also reveal that Wnt3a, a canonical Wnt ligand, increases the expression of Ten-3 through a mechanism dependent on the secretion and activity of the non-canonical ligand Wnt5a. Although our work raises several new questions, our findings seem to demonstrate the upregulation of Ten-3 by Wnt signaling and also suggest that Ten-3 modulation is possible because of crosstalk between the canonical and non-canonical Wnt pathways.
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Fasciculation and elongation zeta/zygin (FEZ) proteins are a family of hub proteins and share many characteristics like high connectivity in interaction networks, they are involved in several cellular processes, evolve slowly and in general have intrinsically disordered regions. In 1985, unc-76 gene was firstly described and involved in axonal growth in C. elegans, and in 1997 Bloom and Horvitz enrolled also the human homologues genes, FEZ1 and FEZ2, in this process. While nematodes possess one gene (unc-76), mammalians have one more copy (FEZ1 and FEZ2). Several animal models have been used to study FEZ family functions like: C. elegans, D. melanogaster, R. novergicus and human cells. Complementation assays were performed and demonstrated the function conservation between paralogues. Human FEZ1 protein is more studied followed by UNC-76 and FEZ2 proteins, respectively. While FEZ1 and UNC-76 shared interaction partners, FEZ2 evolved and increased the number of protein-protein interactions (PPI) with cytoplasmatic partners. FEZ proteins are implicated in intracellular transport, acting as bivalent cargo transport adaptors in kinesin-mediated movement. Especially in light of this cellular function, this family of proteins has been involved in several processes like neuronal development, neurological disorders, viral infection and autophagy. However, nuclear functions of FEZ proteins have been explored as well, due to high content of PPI with nuclear proteins, correlating FEZ1 expression to Sox2 and Hoxb4 gene regulation and retinoic acid signaling. These recent findings open new avenue to study FEZ proteins functions and its involvement in already described processes. This review intends to reunite aspects of evolution, structure, interaction partners and function of FEZ proteins and correlate them to physiological and pathological processes.
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Mitochondria is not only a dynamic organelle that produces ATP, but is also an important contributor to cell functions in both development and cell death processes. These paradoxical functions of mitochondria are partially regulated by the mitochondrial permeability transition pore (mPTP), a high-conductance channel that can induce loss of mitochondrial membrane potential, impairment of cellular calcium homeostasis, oxidative stress, and a decrease in ATP production upon pathological activation. Interestingly, despite their different etiologies, several neurodegenerative diseases and heart ischemic injuries share mitochondrial dysfunction as a common element. Generally, mitochondrial impairment is triggered by calcium deregulation that could lead to mPTP opening and cell death. Several studies have shown that opening of the mPTP not only induces mitochondrial damage and cell death, but is also a physiological mechanism involved in different cellular functions. The mPTP participates in regular calcium-release mechanisms that are required for proper metabolic regulation; it is hypothesized that the transient opening of this structure could be the principal mediator of cardiac and brain development. The mPTP also plays a role in protecting against different brain and cardiac disorders in the elderly population. Therefore, the aim of this work was to discuss different studies that show this controversial characteristic of the mPTP; although mPTP is normally associated with several pathological events, new critical findings suggest its importance in mitochondrial function and cell development.
Assuntos
Cardiomiopatias/patologia , Mitocôndrias/metabolismo , Proteínas de Transporte da Membrana Mitocondrial/metabolismo , Doenças Neurodegenerativas/patologia , Trifosfato de Adenosina/biossíntese , Animais , Cálcio/metabolismo , Coração/embriologia , Coração/crescimento & desenvolvimento , Humanos , Potencial da Membrana Mitocondrial , Camundongos , Poro de Transição de Permeabilidade Mitocondrial , Miócitos Cardíacos/citologia , Estresse Oxidativo/fisiologiaRESUMO
The Wnt signaling pathway plays a role in the development of the central nervous system and growing evidence indicates that Wnts also regulates the structure and function of the adult nervous system. Wnt components are key regulators of a variety of developmental processes, including embryonic patterning, cell specification, and cell polarity. In the nervous system, Wnt signaling also regulates the formation and function of neuronal circuits by controlling neuronal differentiation, axon outgrowth and guidance, dendrite development, synaptic function, and neuronal plasticity. Wnt factors can signal through three very well characterized cascades: canonical or ß-catenin pathway, planar cell polarity pathway and calcium pathway that control different processes. However, divergent downstream cascades have been identified to control neuronal morphogenesis. In the nervous system, the expression of Wnt proteins is a highly controlled process. In addition, deregulation of Wnt signaling has been associated with neurodegenerative diseases. Here, we will review different aspects of neuronal and dendrite maturation, including spinogenesis and synaptogenesis. Finally, the role of Wnt pathway components on Alzheimer's disease will be revised.