The centrosome neither persistently leads migration nor determines the site of axonogenesis in migrating neurons in vivo (original) (raw)
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F1000 - Post-publication peer review of the biomedical literature, 2005
During rodent cortex development, cells born in the medial ganglionic eminence (MGE) of the basal telencephalon reach the embryonic cortex by tangential migration and differentiate as interneurons. Migrating MGE cells exhibit a saltatory progression of the nucleus and continuously extend and retract branches in their neuritic arbor. We have analyzed the migration cycle of these neurons using in vitro models. We show that the nucleokinesis in MGE cells comprises two phases. First, cytoplasmic organelles migrate forward, and second, the nucleus translocates toward these organelles. During the first phase, a large swelling that contains the centrosome and the Golgi apparatus separates from the perinuclear compartment and moves rostrally into the leading neurite, up to 30 m from the waiting nucleus. This long-distance migration is associated with a splitting of the centrioles that line up along a linear Golgi apparatus. It is followed by the second, dynamic phase of nuclear translocation toward the displaced centrosome and Golgi apparatus. The forward movement of the nucleus is blocked by blebbistatin, a specific inhibitor of nonmuscle myosin II. Because myosin II accumulates at the rear of migrating MGE cells, actomyosin contraction likely plays a prominent role to drive forward translocations of the nucleus toward the centrosome. During this phase of nuclear translocation, the leading growth cone either stops migrating or divides, showing a tight correlation between leading edge movements and nuclear movements.
Centrosome localization determines neuronal polarity
Nature, 2005
Neuronal polarization occurs shortly after mitosis. In neurons differentiating in vitro, axon formation follows the segregation of growth-promoting activities to only one of the multiple neurites that form after mitosis 1,2 . It is unresolved whether such spatial restriction makes use of an intrinsic program, like during C. elegans embryo polarization 3 , or is extrinsic and cue-mediated, as in migratory cells 4 . Here we show that in hippocampal neurons in vitro, the axon consistently arises from the neurite that develops first after mitosis. Centrosomes, the Golgi apparatus and endosomes cluster together close to the area where the first neurite will form, which is in turn opposite from the plane of the last mitotic division. We show that the polarized activities of these organelles are necessary and sufficient for neuronal polarization: (1) polarized microtubule polymerization and membrane transport precedes first neurite formation, (2) neurons with more than one centrosome sprout more than one axon and (3) suppression of centrosome-mediated functions precludes polarization. We conclude that asymmetric centrosome-mediated dynamics in the early post-mitotic stage instruct neuronal polarity, implying that pre-mitotic mechanisms with a role in division orientation may in turn participate in this event.
Centrosome Motility Is Essential for Initial Axon Formation in the Neocortex
Journal of Neuroscience, 2010
The mechanisms underlying the normal development of neuronal morphology remain a fundamental question in neurobiology. Studies in cultured neurons have suggested that the position of the centrosome and the Golgi may predict the site of axon outgrowth. During neuronal migration in the developing cortex, however, the centrosome and Golgi are oriented toward the cortical plate at a time when axons grow toward the ventricular zone. In the current work, we use in situ live imaging to demonstrate that the centrosome and the accompanying polarized cytoplasm exhibit apical translocation in newborn cortical neurons preceding initial axon outgrowth. Disruption of centrosomal activity or downregulation of the centriolar satellite protein PCM-1 affects axon formation. We further show that downregulation of the centrosomal protein Cep120 impairs microtubule organization, resulting in increased centrosome motility. Decreased centrosome motility resulting from microtubule stabilization causes an aberrant centrosomal localization, leading to misplaced axonal outgrowth. Our results reveal the dynamic nature of the centrosome in developing cortical neurons, and implicate centrosome translocation and microtubule organization during the multipolar stage as important determinants of axon formation.
Polarity Regulation in Migrating Neurons in the Cortex
Molecular Neurobiology, 2009
The formation of the cerebral cortex requires migration of billions of cells from their birth position to their final destination. A motile cell must have internal polarity in order to move in a specified direction. Locomotory polarity requires the coordinated polymerization of cytoskeletal elements such as microtubules and actin combined with regulated activities of the associated molecular motors. This review is focused on migrating neurons in the developing cerebral cortex, which need to attain internal polarity in order to reach their proper target. The position and dynamics of the centrosome plays an important function in this directed motility. We highlight recent interesting findings connecting polarity proteins with neuronal migration events regulated by the microtubuleassociated molecular motor, cytoplasmic dynein.
Emerging roles of the centrosome in neuronal development
The role of the centrosome-a microtubule-organizing center-in neuronal development has been under scrutiny and is controversial. The function and position of the centrosome have been shown to play an important role in selecting the position of axon outgrowth in cultured neurons and in situ. However, other studies have shown that axonal growth is independent of centrosomal functions. Recent discoveries define the centrosome as an F-actin organizing organelle in various cell types; thus, giving a whole new perspective to the role of the centrosome in lymphocyte polarity, cell division, and neuronal development. These discoveries compel the need to revisit centrosomal functions by investigating the fundamental mechanisms that regulate centrosomal F-actin remodeling during neuronal differentiation and polarization. In this review, we summarize the up-to-date knowledge regarding the function of the centrosome in neuronal differentiation. We put special emphasis on recent findings describing the centrosome as an F-actin organizing center. Additionally, with the available data regarding centrosome, microtubules and F-actin organization, we provide a model on how centrosomal F-actin could be modulating neuronal differentiation and polarity. K E Y W O R D S centrosome, F-actin, neuronal differentiation 1 | INTRODUCTION Neurons are complex cells with distinct functional domains for information processing: Dendrites receive synaptic input and relay signals to the soma, where the integrated information is transmitted via the axon over short or long distances. Differentiating neurons follow an intricate process during which one of the neurites is specified as an axon and the remaining into dendrites. Axon specification is the defining step for neuronal polarization, this event defines the connectivity of a neuron for the rest of its lifetime. We, however, do not completely understand the mechanisms behind the process of axon specification. There is contradicting research suggesting either cellintrinsic or -extrinsic regulating factors of neuronal polarization.
Guiding neuronal cell migrations
Cold Spring Harbor perspectives in biology, 2010
Neuronal migration is, along with axon guidance, one of the fundamental mechanisms underlying the wiring of the brain. As other organs, the nervous system has acquired the ability to grow both in size and complexity by using migration as a strategy to position cell types from different origins into specific coordinates, allowing for the generation of brain circuitries. Guidance of migrating neurons shares many features with axon guidance, from the use of substrates to the specific cues regulating chemotaxis. There are, however, important differences in the cell biology of these two processes. The most evident case is nucleokinesis, which is an essential component of migration that needs to be integrated within the guidance of the cell. Perhaps more surprisingly, the cellular mechanisms underlying the response of the leading process of migrating cells to guidance cues might be different to those involved in growth cone steering, at least for some neuronal populations.
The Role of Tangential Migration in the Establishment of Mammalian Cortex
Neuron, 2001
The importance of the boundaries between these mor-Case Western Reserve University School phological subdivisions is emphasized by the expresof Medicine sion patterns of a number of genes: Gli3, Ngn1, and University Hospitals Research Institute Ngn2 in cortex; Mash1, Dlx1, and Dlx2 in both ganglionic Cleveland, Ohio 44106 eminences; and Nkx2.1 in the MGE alone (see Figure 1). (Wilson and Rubenstein, 2000)