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ELife Apr 2021Diaphanous (DIAPH) three (DIAPH3) is a member of the formin proteins that have the capacity to nucleate and elongate actin filaments and, therefore, to remodel the...
Diaphanous (DIAPH) three (DIAPH3) is a member of the formin proteins that have the capacity to nucleate and elongate actin filaments and, therefore, to remodel the cytoskeleton. DIAPH3 is essential for cytokinesis as its dysfunction impairs the contractile ring and produces multinucleated cells. Here, we report that DIAPH3 localizes at the centrosome during mitosis and regulates the assembly and bipolarity of the mitotic spindle. DIAPH3-deficient cells display disorganized cytoskeleton and multipolar spindles. DIAPH3 deficiency disrupts the expression and/or stability of several proteins including the kinetochore-associated protein SPAG5. DIAPH3 and SPAG5 have similar expression patterns in the developing brain and overlapping subcellular localization during mitosis. Knockdown of SPAG5 phenocopies DIAPH3 deficiency, whereas its overexpression rescues the DIAHP3 knockdown phenotype. Conditional inactivation of in mouse cerebral cortex profoundly disrupts neurogenesis, depleting cortical progenitors and neurons, leading to cortical malformation and autistic-like behavior. Our data uncover the uncharacterized functions of DIAPH3 and provide evidence that this protein belongs to a molecular toolbox that links microtubule dynamics during mitosis to aneuploidy, cell death, fate determination defects, and cortical malformation.
Topics: Animals; Behavior, Animal; Cell Cycle Proteins; Cell Line, Tumor; Cerebral Cortex; Feeding Behavior; Formins; Gene Expression Regulation, Developmental; Genotype; Humans; Locomotion; Maze Learning; Mice; Mice, Knockout; Microtubules; Mitosis; NIH 3T3 Cells; Neurogenesis; Neurons; Phenotype; Social Behavior; Spindle Apparatus
PubMed: 33899739
DOI: 10.7554/eLife.61974 -
Frontiers in Cellular Neuroscience 2014Most neurons migrate with an elongated, "bipolar" morphology, extending a long leading process that explores the environment. However, when immature projection neurons... (Review)
Review
Most neurons migrate with an elongated, "bipolar" morphology, extending a long leading process that explores the environment. However, when immature projection neurons enter the intermediate zone (IZ) of the neocortex they become "multipolar". Multipolar cells extend and retract cytoplasmic processes in different directions and move erratically-sideways, up and down. Multipolar cells extend axons while they are in the lower half of the IZ. Remarkably, the cells then resume radial migration: they reorient their centrosome and Golgi apparatus towards the pia, transform back to bipolar morphology, and commence locomotion along radial glia (RG) fibers. This reorientation implies the existence of directional signals in the IZ that are ignored during the multipolar stage but sensed after axonogenesis. In vivo genetic manipulation has implicated a variety of candidate directional signals, cell surface receptors, and signaling pathways, that may be involved in polarizing multipolar cells and stabilizing a pia-directed leading process for radial migration. Other signals are implicated in starting multipolar migration and triggering axon outgrowth. Here we review the molecules and mechanisms that regulate multipolar migration, and also discuss how multipolar migration affects the orderly arrangement of neurons in layers and columns in the developing neocortex.
PubMed: 25452716
DOI: 10.3389/fncel.2014.00386 -
Frontiers in Cellular Neuroscience 2020Cellular protein homeostasis, or proteostasis, is indispensable to the survival and function of all cells. Distinct from other cell types, neurons are long-lived,... (Review)
Review
Cellular protein homeostasis, or proteostasis, is indispensable to the survival and function of all cells. Distinct from other cell types, neurons are long-lived, exhibiting architecturally complex and diverse multipolar projection morphologies that can span great distances. These properties present unique demands on proteostatic machinery to dynamically regulate the neuronal proteome in both space and time. Proteostasis is regulated by a distributed network of cellular processes, the proteostasis network (PN), which ensures precise control of protein synthesis, native conformational folding and maintenance, and protein turnover and degradation, collectively safeguarding proteome integrity both under homeostatic conditions and in the contexts of cellular stress, aging, and disease. Dendrites are equipped with distributed cellular machinery for protein synthesis and turnover, including dendritically trafficked ribosomes, chaperones, and autophagosomes. The PN can be subdivided into an adaptive network of three major functional pathways that synergistically govern protein quality control through the action of (1) protein synthesis machinery; (2) maintenance mechanisms including molecular chaperones involved in protein folding; and (3) degradative pathways (, Ubiquitin-Proteasome System (UPS), endolysosomal pathway, and autophagy. Perturbations in any of the three arms of proteostasis can have dramatic effects on neurons, especially on their dendrites, which require tightly controlled homeostasis for proper development and maintenance. Moreover, the critical importance of the PN as a cell surveillance system against protein dyshomeostasis has been highlighted by extensive work demonstrating that the aggregation and/or failure to clear aggregated proteins figures centrally in many neurological disorders. While these studies demonstrate the relevance of derangements in proteostasis to human neurological disease, here we mainly review recent literature on homeostatic developmental roles the PN machinery plays in the establishment, maintenance, and plasticity of stable and dynamic dendritic arbors. Beyond basic housekeeping functions, we consider roles of PN machinery in protein quality control mechanisms linked to dendritic plasticity (, dendritic spine remodeling during LTP); cell-type specificity; dendritic morphogenesis; and dendritic pruning.
PubMed: 33013325
DOI: 10.3389/fncel.2020.00264 -
Frontiers in Cellular Neuroscience 2019Cell polarity refers to the asymmetric distribution of signaling molecules, cellular organelles, and cytoskeleton in a cell. Neural progenitors and neurons are highly... (Review)
Review
Cell polarity refers to the asymmetric distribution of signaling molecules, cellular organelles, and cytoskeleton in a cell. Neural progenitors and neurons are highly polarized cells in which the cell membrane and cytoplasmic components are compartmentalized into distinct functional domains in response to internal and external cues that coordinate polarity and behavior during development and disease. In neural progenitor cells, polarity has a prominent impact on cell shape and coordinate several processes such as adhesion, division, and fate determination. Polarity also accompanies a neuron from the beginning until the end of its life. It is essential for development and later functionality of neuronal circuitries. During development, polarity governs transitions between multipolar and bipolar during migration of postmitotic neurons, and directs the specification and directional growth of axons. Once reaching final positions in cortical layers, neurons form dendrites which become compartmentalized to ensure proper establishment of neuronal connections and signaling. Changes in neuronal polarity induce signaling cascades that regulate cytoskeletal changes, as well as mRNA, protein, and vesicle trafficking, required for synapses to form and function. Hence, defects in establishing and maintaining cell polarity are associated with several neural disorders such as microcephaly, lissencephaly, schizophrenia, autism, and epilepsy. In this review we summarize the role of polarity genes in cortical development and emphasize the relationship between polarity dysfunctions and cortical malformations.
PubMed: 31213986
DOI: 10.3389/fncel.2019.00244 -
Frontiers in Neuroscience 2014The formation of the six-layered structure of the mammalian cortex via the inside-out pattern of neuronal migration is fundamental to neocortical functions.... (Review)
Review
The formation of the six-layered structure of the mammalian cortex via the inside-out pattern of neuronal migration is fundamental to neocortical functions. Extracellular cues such as Reelin induce intracellular signaling cascades through the protein phosphorylation. Migrating neurons also have intrinsic machineries to regulate cytoskeletal proteins and adhesion properties. Protein phosphorylation regulates these processes. Moreover, the balance between phosphorylation and dephosphorylation is modified by extracellular cues. Multipolar-bipolar transition, radial glia-guided locomotion and terminal translocation are critical steps of radial migration of cortical pyramidal neurons. Protein kinases such as Cyclin-dependent kinase 5 (Cdk5) and c-Jun N-terminal kinases (JNKs) involve these steps. In this review, I shall give an overview the roles of protein kinases in neuronal migration.
PubMed: 25628530
DOI: 10.3389/fnins.2014.00458 -
Cells Jun 2019Neuronal migration is essential for the orchestration of brain development and involves several contiguous steps: interkinetic nuclear movement (INM), multipolar-bipolar... (Review)
Review
Neuronal migration is essential for the orchestration of brain development and involves several contiguous steps: interkinetic nuclear movement (INM), multipolar-bipolar transition, locomotion, and translocation. Growing evidence suggests that Rho GTPases, including RhoA, Rac, Cdc42, and the atypical Rnd members, play critical roles in neuronal migration by regulating both actin and microtubule cytoskeletal components. This review focuses on the spatiotemporal-specific regulation of Rho GTPases as well as their regulators and effectors in distinct steps during the neuronal migration process. Their roles in bridging extracellular signals and cytoskeletal dynamics to provide optimal structural support to the migrating neurons will also be discussed.
Topics: Adherens Junctions; Animals; Cell Movement; Ependymoglial Cells; Humans; Neurogenesis; Neurons; cdc42 GTP-Binding Protein; rho GTP-Binding Proteins
PubMed: 31185627
DOI: 10.3390/cells8060568 -
Frontiers in Neuroscience 2015Cortical neurons consist of excitatory projection neurons and inhibitory GABAergic interneurons, whose connections construct highly organized neuronal circuits that... (Review)
Review
Cortical neurons consist of excitatory projection neurons and inhibitory GABAergic interneurons, whose connections construct highly organized neuronal circuits that control higher order information processing. Recent progress in live imaging has allowed us to examine how these neurons differentiate during development in vivo or in in vivo-like conditions. These analyses have revealed how the initial steps of polarization, in which neurons establish an axon, occur. Interestingly, both excitatory and inhibitory cortical neurons establish neuronal polarity de novo by undergoing a multipolar stage reminiscent of the manner in which polarity formation occurs in hippocampal neurons in dissociated culture. In this review, we focus on polarity formation in cortical neurons and describe their typical morphology and dynamic behavior during the polarization period. We also discuss cellular and molecular mechanisms underlying polarization, with reference to polarity formation in dissociated hippocampal neurons in vitro.
PubMed: 25904841
DOI: 10.3389/fnins.2015.00116 -
Frontiers in Cellular Neuroscience 2017The cerebral cortex is composed of billions of neurons that can grossly be subdivided into two broad classes: inhibitory GABAergic interneurons and excitatory... (Review)
Review
The cerebral cortex is composed of billions of neurons that can grossly be subdivided into two broad classes: inhibitory GABAergic interneurons and excitatory glutamatergic neurons. The majority of cortical neurons in mammals are the excitatory type and they are the main focus of this review article. Like many of the cells in multicellular organisms, fully differentiated neurons are both morphologically and functionally polarized. However, they go through several changes in polarity before reaching this final mature differentiated state. Neurons are derived from polarized neuronal progenitor/stem cells and their commitment to neuronal fate is decided by cellular and molecular asymmetry during their last division in the neurogenic zone. They migrate from their birthplace using so-called multipolar migration, during which they switch direction of movement several times, and repolarize for bipolar migration when the axon is specified. Therefore, neurons have to break their previous symmetry, change their morphology and adequately respond to polarizing signals during migration in order to reach the correct position in the cortex and start making connections. Finally, the dendritic tree is elaborated and the axon/dendrite morphological polarity is set. Here we will describe the function, establishment and maintenance of polarity during the different developmental steps starting from neural stem cell (NSC) division, neuronal migration and axon specification at embryonic developmental stages.
PubMed: 28670267
DOI: 10.3389/fncel.2017.00163