scholarly journals Mitochondrial Dynamics: impact on adult neural stem cell fate

2020 ◽  
Author(s):  
Rita Soares ◽  
Diogo M. Lourenço ◽  
Jonathan Verduyckt ◽  
Ana M. Sebastião ◽  
Sara Xapelli ◽  
...  
Keyword(s):  
Cell Fate ◽  
Molecular Mechanisms ◽  
Mitochondrial Dynamics ◽  
Culture Conditions ◽  
Neurological Deficits ◽  
Mammalian Brain ◽  
Seeding Density ◽  
Brain Repair ◽  
Adult Neural Stem Cell

Neural stem cells (NSCs) are found in discrete regions of the mammalian brain. During adulthood, NSCs can be a source of new neurons and oligodendrocytes in neurological disorders. However, these newborn cells are not sufficient to overcome the neurological deficits involved by neural loss. Therefore, the identification of novel mechanisms responsible for modulating NSC fate represent a major key issue for future brain repair strategies. Several studies suggest that mitochondria have an important role in regulating NSC differentiation and lineage determination. However, the molecular mechanisms involved in this regulation remain unknown. Hence, our work aims to dissect how mitochondria biogenesis and dynamics can modulate the NSC differentiation into neurons or oligodendrocytes. For this, NSCs were obtained by isolating subventricular zone (SVZ) and dentate gyrus (DG) cells from P1-3 mouse models. Seeding density, culture conditions and number of passages were determined. Moreover, the multipotency of SVZ/DG-derived NSPCs, obtained from different passages, was also accessed. Additionally, expression of proteins involved in mitochondrial biogenesis and fusion/fission appear altered during NSPC differentiation, while mitochondrial network revealed different morphologies in cells from different lineages. The results obtained will provide novel findings concerning the role of mitochondrial dynamics in NSC fate.

scholarly journals Brain micro-ecologies: neural stem cell niches in the adult mammalian brain

2007 ◽  
Vol 363 (1489) ◽  
pp. 123-137 ◽  
Author(s):  
Patricio A Riquelme ◽  
Elodie Drapeau ◽  
Fiona Doetsch
Keyword(s):  
Stem Cell ◽  
Cell Fate ◽  
Neural Stem Cell ◽  
Subventricular Zone ◽  
Hippocampal Formation ◽  
Mammalian Brain ◽  
Adult Neural Stem Cell ◽  
Stem Cell Fate ◽  
Stem Cell Niches ◽  
Adult Mammalian Brain

Neurogenesis persists in two germinal regions in the adult mammalian brain, the subventricular zone of the lateral ventricles and the subgranular zone in the hippocampal formation. Within these two neurogenic niches, specialized astrocytes are neural stem cells, capable of self-renewing and generating neurons and glia. Cues within the niche, from cell–cell interactions to diffusible factors, are spatially and temporally coordinated to regulate proliferation and neurogenesis, ultimately affecting stem cell fate choices. Here, we review the components of adult neural stem cell niches and how they act to regulate neurogenesis in these regions.

scholarly journals Mitochondrial Fusion/Fission, Transport and Autophagy in Parkinson's Disease: When Mitochondria Get Nasty

2011 ◽  
Vol 2011 ◽  
pp. 1-13 ◽  
Author(s):  
Daniela M. Arduíno ◽  
A. Raquel Esteves ◽  
Sandra M. Cardoso
Keyword(s):  
Parkinson’S Disease ◽  
Parkinson's Disease ◽  
Mitochondrial Dysfunction ◽  
Molecular Basis ◽  
Molecular Mechanisms ◽  
Mitochondrial Dynamics ◽  
Growing Body ◽  
Parkinsonian Disorders ◽  
Mitochondrial Trafficking

Understanding the molecular basis of Parkinson's disease (PD) has proven to be a major challenge in the field of neurodegenerative diseases. Although several hypotheses have been proposed to explain the molecular mechanisms underlying the pathogenesis of PD, a growing body of evidence has highlighted the role of mitochondrial dysfunction and the disruption of the mechanisms of mitochondrial dynamics in PD and other parkinsonian disorders. In this paper, we comment on the recent advances in how changes in the mitochondrial function and mitochondrial dynamics (fusion/fission, transport, and clearance) contribute to neurodegeneration, specifically focusing on PD. We also evaluate the current controversies in those issues and discuss the role of fusion/fission dynamics in the mitochondrial lifecycle and maintenance. We propose that cellular demise and neurodegeneration in PD are due to the interplay between mitochondrial dysfunction, mitochondrial trafficking disruption, and impaired autophagic clearance.

scholarly journals Function and Plasticity of Electrical Synapses in the Mammalian Brain: Role of Non-Junctional Mechanisms

2021 ◽  
Author(s):  
Sebastian Curti ◽  
Federico Davoine ◽  
Antonella Dapino
Keyword(s):  
Molecular Mechanisms ◽  
Mammalian Brain ◽  
Synaptic Membrane ◽  
Electrical Transmission ◽  
Electrical Synapses ◽  
Electrophysiological Properties ◽  
Voltage Dependent ◽  
Theoretical Evidence ◽  
Circuit Function

Electrical transmission between neurons is largely mediated by gap junctions. These junctions allow the direct flow of electric current between neurons, and in mammals are mostly composed of the protein connexin (Cx)36. Circuits of electrically coupled neurons are widespread in these animals, plus, experimental and theoretical evidence supports the notion that, beyond synchronicity, these circuits are able to perform sophisticated operations like lateral excitation and inhibition, noise reduction, as well as the ability to selectively respond upon coincident excitatory inputs. Although once considered stereotyped and unmodifiable, we now know that electrical synapses are subject to modulation and, by reconfiguring neural circuits, these modulations can alter relevant operations. The strength of electrical synapses depends on gap junction conductance, as well as on its functional interaction with the electrophysiological properties of coupled neurons. In particular, voltage dependent channels of the non-synaptic membrane critically determine the efficacy of transmission at these contacts. Consistently, modulatory actions on these channels have been shown to represent relevant mechanisms of plasticity of electrical synaptic transmission. Here we review recent evidence on the regulation of electrical synapses of mammals, the underlying molecular mechanisms, and the possible ways in which they affect circuit function.

scholarly journals Notch1 is required for neuronal and glial differentiation in the cerebellum

Development ◽  
2002 ◽  
Vol 129 (2) ◽  
pp. 373-385 ◽  
Author(s):  
Simone Lütolf ◽  
Freddy Radtke ◽  
Michel Aguet ◽  
Ueli Suter ◽  
Verdon Taylor
Keyword(s):  
Central Nervous System ◽  
Cell Fate ◽  
Progenitor Cell ◽  
Mammalian Brain ◽  
Glial Differentiation ◽  
Gene Ablation ◽  
Neuroepithelial Cells ◽  
Vertebrate Central Nervous System

The mechanisms that guide progenitor cell fate and differentiation in the vertebrate central nervous system (CNS) are poorly understood. Gain-of-function experiments suggest that Notch signaling is involved in the early stages of mammalian neurogenesis. On the basis of the expression of Notch1 by putative progenitor cells of the vertebrate CNS, we have addressed directly the role of Notch1 in the development of the mammalian brain. Using conditional gene ablation, we show that loss of Notch1 results in premature onset of neurogenesis by neuroepithelial cells of the midbrain-hindbrain region of the neural tube. Notch1-deficient cells do not complete differentiation but are eliminated by apoptosis, resulting in a reduced number of neurons in the adult cerebellum. We have also analyzed the effects of Notch1 ablation on gliogenesis in vivo. Our results show that Notch1 is required for both neuron and glia formation and modulates the onset of neurogenesis within the cerebellar neuroepithelium.

scholarly journals Wnt-Frizzled Signaling Regulates Activity-Mediated Synapse Formation

2021 ◽  
Vol 14 ◽  
Author(s):  
Samuel Teo ◽  
Patricia C. Salinas
Keyword(s):  
Wnt Signaling ◽  
Neuronal Activity ◽  
Molecular Mechanisms ◽  
Synapse Formation ◽  
Model Systems ◽  
Mammalian Brain ◽  
Excitatory Synapses ◽  
Wnt Ligands

The formation of synapses is a tightly regulated process that requires the coordinated assembly of the presynaptic and postsynaptic sides. Defects in synaptogenesis during development or in the adult can lead to neurodevelopmental disorders, neurological disorders, and neurodegenerative diseases. In order to develop therapeutic approaches for these neurological conditions, we must first understand the molecular mechanisms that regulate synapse formation. The Wnt family of secreted glycoproteins are key regulators of synapse formation in different model systems from invertebrates to mammals. In this review, we will discuss the role of Wnt signaling in the formation of excitatory synapses in the mammalian brain by focusing on Wnt7a and Wnt5a, two Wnt ligands that play an in vivo role in this process. We will also discuss how changes in neuronal activity modulate the expression and/or release of Wnts, resulting in changes in the localization of surface levels of Frizzled, key Wnt receptors, at the synapse. Thus, changes in neuronal activity influence the magnitude of Wnt signaling, which in turn contributes to activity-mediated synapse formation.

scholarly journals ATM Kinase-Dependent Regulation of Autophagy: A Key Player in Senescence?

2021 ◽  
Vol 8 ◽  
Author(s):  
Venturina Stagni ◽  
Alessandra Ferri ◽  
Claudia Cirotti ◽  
Daniela Barilà
Keyword(s):  
Cell Fate ◽  
Ataxia Telangiectasia ◽  
Molecular Mechanisms ◽  
Genetic Disorder ◽  
Premature Aging ◽  
Ataxia Telangiectasia Mutated ◽  
Atm Kinase ◽  
Cellular Environment ◽  
Key Factor

Increasing evidence suggests a strong interplay between autophagy and genomic stability. Recently, several papers have demonstrated a molecular connection between the DNA Damage Response (DDR) and autophagy and have explored how this link influences cell fate and the choice between apoptosis and senescence in response to different stimuli. The aberrant deregulation of this interplay is linked to the development of pathologies, including cancer and neurodegeneration. Ataxia-telangiectasia mutated kinase (ATM) is the product of a gene that is lost in Ataxia-Telangiectasia (A-T), a rare genetic disorder characterized by ataxia and cerebellar neurodegeneration, defects in the immune response, higher incidence of lymphoma development, and premature aging. Importantly, ATM kinase plays a central role in the DDR, and it can finely tune the balance between senescence and apoptosis: activated ATM promotes autophagy and in particular sustains the lysosomal-mitochondrial axis, which in turn promotes senescence and inhibits apoptosis. Therefore, ATM is the key factor that enables cells to escape apoptosis by entering senescence through modulation of autophagy. Importantly, unlike apoptotic cells, senescent cells are viable and have the ability to secrete proinflammatory and mitogenic factors, thus influencing the cellular environment. In this review we aim to summarize recent advances in the understanding of molecular mechanisms linking DDR and autophagy to senescence, pointing out the role of ATM kinase in these cellular responses. The significance of this regulation in the pathogenesis of Ataxia-Telangiectasia will be discussed.

scholarly journals The Neurobiology of Selenium: Looking Back and to the Future

2021 ◽  
Vol 15 ◽  
Author(s):  
Ulrich Schweizer ◽  
Simon Bohleber ◽  
Wenchao Zhao ◽  
Noelia Fradejas-Villar
Keyword(s):  
Cell Biology ◽  
Molecular Mechanisms ◽  
Human Genetics ◽  
Epileptic Seizures ◽  
Cell Types ◽  
Mammalian Brain ◽  
The Individual ◽  
The Brain ◽  
Looking Back

Eighteen years ago, unexpected epileptic seizures in Selenop-knockout mice pointed to a potentially novel, possibly underestimated, and previously difficult to study role of selenium (Se) in the mammalian brain. This mouse model was the key to open the field of molecular mechanisms, i.e., to delineate the roles of selenium and individual selenoproteins in the brain, and answer specific questions like: how does Se enter the brain; which processes and which cell types are dependent on selenoproteins; and, what are the individual roles of selenoproteins in the brain? Many of these questions have been answered and much progress is being made to fill remaining gaps. Mouse and human genetics have together boosted the field tremendously, in addition to traditional biochemistry and cell biology. As always, new questions have become apparent or more pressing with solving older questions. We will briefly summarize what we know about selenoproteins in the human brain, glance over to the mouse as a useful model, and then discuss new questions and directions the field might take in the next 18 years.

scholarly journals Androgen action in cell fate and communication during prostate development at single-cell resolution

Development ◽  
2020 ◽  
pp. dev.196048
Author(s):  
Dong-Hoon Lee ◽  
Adam W. Olson ◽  
Jinhui Wang ◽  
Won Kyung Kim ◽  
Jiaqi Mi ◽  
...  
Keyword(s):  
Single Cell ◽  
Signaling Pathways ◽  
Cell Fate ◽  
Molecular Mechanisms ◽  
Bud Formation ◽  
Master Regulators ◽  
Prostate Development ◽  
Dynamic Cell ◽  
Cell Signaling Networks

Androgens/androgen receptor (AR) mediated signaling pathways are essential for prostate development, morphogenesis, and regeneration. Specifically, stromal AR-signaling has been shown to be essential for prostatic initiation. However, the molecular mechanisms underlying AR-initiated mesenchymal-epithelial interactions in prostate development remain unclear. Here, using a newly generated mouse model, we directly addressed the fate and role of genetically marked AR-expressing cells during embryonic prostate development. Androgen signaling-initiated signaling pathways were identified in mesenchymal niche populations at single cell transcriptomic resolution. The dynamic cell-signaling networks regulated by stromal AR were characterized in regulating prostatic epithelial bud formation. Pseudotime analyses further revealed the differentiation trajectory and fate of AR-expressing cells in both prostatic mesenchymal and epithelial cell populations. Specifically, the cellular properties of Zeb1-expressing progenitors were assessed. Selective deletion of AR signaling in a subpopulation mesenchymal rather than epithelial cells dysregulates the expression of the master regulators and significantly impairs prostatic bud formation. These data provide novel, high-resolution evidence demonstrating the important role of mesenchymal androgen signaling as cellular niches controlling prostate early development by initiating dynamic mesenchyme-epithelia cell interactions.

The Role of ASIC1a in Epilepsy: A Potential Therapeutic Target

2021 ◽  
Vol 19 ◽  
Author(s):  
Yu Cheng ◽  
Wuqiong Zhang ◽  
Yue Li ◽  
Ting Jiang ◽  
Buhajar Mamat ◽  
...  
Keyword(s):  
Therapeutic Target ◽  
Molecular Mechanisms ◽  
Brain Diseases ◽  
Mammalian Brain ◽  
Acid Sensing Ion Channels ◽  
Promising Therapeutic Target ◽  
Pathological Mechanism ◽  
Tissue Acidosis ◽  
Epileptogenic Foci

Background: Epilepsy represents one of the most common brain diseases among humans. Tissue acidosis is a common phenomenon in epileptogenic foci. This said, its roles in epileptogenesis remain unclear. Acid-sensing ion channel-1a (ASIC1a) represents a potential way to assess new therapies. ASIC1a, mainly expressed in the mammalian brain, is a type of protein-gated cation channel. It has been shown to play an important role in the pathological mechanism of various diseases, including stroke, epilepsy, and multiple sclerosis. Methods: Data were collected from Web of Science, Medline, PubMed, through searching for these keywords: "Acid-sensing ion channels 1a" or "ASIC1a" and "epilepsy" or "seizure". Results: The role of ASIC1a in epilepsy remains controversial; it may represent a promising therapeutic target of epilepsy. Conclusion:This review is intended to provide an overview of the structure, trafficking, and molecular mechanisms of ASIC1a in order to further elucidate the role of ASIC1a in epilepsy.

scholarly journals Protein Disulfide Isomerase Superfamily in Disease and the Regulation of Apoptosis

2014 ◽  
Vol 1 (1) ◽  
Author(s):  
C. Grek ◽  
D.M. Townsend
Keyword(s):  
Protein Folding ◽  
Er Stress ◽  
Cell Fate ◽  
Molecular Chaperones ◽  
Molecular Mechanisms ◽  
Disulfide Isomerases ◽  
Apoptotic Pathways ◽  
Er Homeostasis ◽  
Protein Disulfide

AbstractCellular homeostasis requires the balance of a multitude of signaling cascades that are contingent upon the essential proteins being properly synthesized, folded and delivered to appropriate subcellular locations. In eukaryotic cells the endoplasmic reticulum (ER) is a specialized organelle that is the central site of synthesis and folding of secretory, membrane and a number of organelletargeted proteins. The integrity of protein folding is enabled by the presence of ATP, Ca++, molecular chaperones, as well as an oxidizing redox environment. The imbalance between the load and capacity of protein folding results in a cellular condition known as ER stress. Failure of these pathways to restore ER homeostasis results in the activation of apoptotic pathways. Protein disulfide isomerases (PDI) compose a superfamily of oxidoreductases that have diverse sequences and are localized in the ER, nucleus, cytosol, mitochondria and cell membrane. The PDI superfamily has multiple functions including, acting as molecular chaperones, protein-binding partners, and hormone reservoirs. Recently , PDI family members have been implicated in the regulation of apoptotic signaling events. The complexities underlying the molecular mechanisms that define the switch from pro-survival to pro-death response are evidenced by recent studies that reveal the roles of specific chaperone proteins as integration points in signaling pathways that determine cell fate. The following review discusses the dual role of PDI in cell death and survival during ER stress.

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