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Cellular Migration And Formation Of Neuronal Connections Pdf

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The development of the nervous system , or neural development , or neurodevelopment , refers to the processes that generate, shape, and reshape the nervous system of animals, from the earliest stages of embryonic development to adulthood.

In those silly movie star sunglasses, she still got a couple of lucky hits. His knuckles turned white as he tightened his grip on the steering wheel. It was as if something were eating away at his gut, sharp teeth gnawing at him. He felt it slithering down the back of his legs, wetting his socks.

Neuronal Migration During Development of the Cerebellum

Many neurons resemble other cells in developing embryos in migrating long distances before they differentiate. However, despite shared basic machinery, neurons differ from other migrating cells. Most dramatically, migrating neurons have a long and dynamic leading process, and may extend an axon from the rear while they migrate. Neurons must coordinate the extension and branching of their leading processes, cell movement with axon specification and extension, switching between actin and microtubule motors, and attachment and recycling of diverse adhesion proteins.

New research is needed to fully understand how migration of such morphologically complicated cells is coordinated over space and time. Nervous systems are the organs through which animals perceive, interpret, and respond to the world around them. They consist of specialized, electrically active cells connected together in networks.

Essentially, all nervous systems develop by four main stages: the proliferation of progenitors in an epithelium, the specification of neurons and glia, the growth and guidance of axons and dendrites, and the development and refinement of electrical and chemical synapses.

However, some more complex nervous systems, including those of vertebrates, have another stage in which newly specified neurons migrate before they differentiate and form synapses. Some migrations cover long distances—up to thousands of cell diameters—and follow complex routes, changing direction at landmarks along the way a key to the major migratory routes, terminology, and abbreviations is provided in Box 1 and Fig.

Because they migrate, neurons from different proliferative zones, and correspondingly distinct lineages and genetic programs, are able to position close to each other and communicate, potentially increasing efficiency.

In addition, different types of neurons arrive at a particular location at different times during development, so circuits are established in a specific order. For these reasons, it is generally thought that neuron migrations facilitate circuit formation and improve nervous system function, although this hypothesis has not been critically tested by the appropriate mutation studies.

Neuron migration routes. The brain develops from the anterior end of the neural tube: a pseudo-stratified epithelial tube with its apical surface inside and basal surface outside. Neuroepithelial cells, known for much of development as radial glia RG , span the wall of the neural tube with their apical junctional complexes at the ventricle—the fluid-filled center of the neural tube—and long processes extending to the pia—a basal lamina surrounding the tube.

RG cell bodies lie close to the ventricle and undergo inter-kinetic nuclear movement IKNM linked to the cell cycle, moving basally toward the pia during G1 and apically toward the ventricle during G2 Fig. Asymmetric divisions of RG give rise to post-mitotic neurons or intermediate progenitors at the ventricular surface. However, in many other regions, newborn neurons actively migrate away from the ventricle. Neuron migrations are broadly classified as radial parallel to RG or tangential orthogonal to RG, either around the circumference of the neural tube or along its length.

Radial migrations include the glial-guided locomotion phase and glia-independent somal translocation phase of cortical projection neurons CPNs; Fig. Tangential migrations include cortical interneurons in the marginal zone and intermediate zone CINs; Fig. Some migrations are hard to classify: late-stage CINs switch from tangential to radial migration into the neocortex Fig. Migrations are termed neurophilic if they follow axons of other neurons, or gliophilic if they follow glia fibers.

Gliophilic migrations include the locomotion phase of CPN migration Fig. Some stages of pontine neuron migration may be neurophilic. Some tangential migrations occur in direct contact with the extracellular matrix of the pia. Major neuron migrations in the developing rodent brain. Transverse sections A and B through the developing rodent brain top.

Top panels show the migration routes and bottom panels show the types of migration. The colors of arrows in the top panels correspond to the colors of cells in the bottom panels. A The neocortex. Cortical interneurons CINs, red migrate tangentially along the marginal zone 1 and intermediate zone 2 from their origins in the basal forebrain. Later they migrate into the cortical plate 3. Cortical projection neurons CPN, blue migrate through three phases: multipolar 1 , locomotion 2 , and somal translocation 3.

B The cerebellum and pons. Granule cell precursors red migrate in the marginal zone, forming a granule cell layer. Post-mitotic granule cells GCs, orange migrate radially inward along Bergmann glia steps 1, 2, and 3 , leaving a bifurcated axon behind. Pontine and other precerebellar neurons purple migrate tangentially in the marginal zone of the pons.

Note that these migrations do not all occur at the same time. This short review presents an overview of neuron migration mechanisms for the cell biologist. For brevity, the short-range and long-range extracellular cues that guide neurons are not discussed; many of the same cues that guide neurons also guide axon growth cones and have been reviewed in depth recently Kolodkin and Tessier-Lavigne, ; Vitriol and Zheng, Collective cell migrations and migrations in the peripheral nervous system are also ignored.

Instead, we discuss the cellular machinery used by neurons migrating in the developing central nervous system. We focus on aspects that are peculiar or exaggerated in neurons compared with other cells: the long leading process, the linkage between the centrosome and nucleus, the use of microtubule motors and actomyosin to move the nucleus, and the variety of adhesion proteins and attachment points for traction.

Not all neurons are alike, however, and exhibit almost as much variation in their migration as slime molds, keratinocytes, fibroblasts, and other cells commonly used as model systems. In addition to describing these differences, where possible we provide somewhat speculative unifying hypotheses to bring out common themes. Migrating neurons generally have a long leading process, tipped by dynamic filopodia and lamellipodia, which resembles a growth cone on a dendrite or axon.

In some neurons, the leading process is branched and dynamic, with different branches growing and collapsing as migration proceeds, whereas in others there is a single, stable leading process that moves forward continuously at the tip.

Diverse mechanisms regulate stabilization and guidance of the leading process. Highly branched, dynamic leading processes are characteristic of several types of neurons that migrate tangentially, including cortical interneurons CINs , pontine neurons, and neuroblasts in the rostral migratory stream Bellion et al. Whereas a single growth cone can only compare the concentrations of attractant or repellant across its width J.

Zheng et al. Indeed, the leading process does not turn when the source of attractant changes Ward et al. Rather, branches are selectively stabilized based on proximity to the source of attractant: the branch whose growth cone is nearer the attractant is stabilized while others retract Fig. A dilation in front of the nucleus, containing the centrosome and Golgi, translocates to the branch point and then into the dominant process, with the nucleus following behind Fig. Competition between different branches also steers pontine neurons from tangential to radial paths Watanabe and Murakami, Thus, selective stabilization of different growth cones determines the direction for moving the centrosome and nucleus.

Morphology and functions of the leading process. A The elaborate leading processes of tangentially migrating neurons are continuously remodeled as migration progresses, with individual branches growing and collapsing. A growth cone in a higher concentration of chemoattractant generates a stronger signal and becomes dominant. Presumably, the cell has a mechanism to compare the signals from different growth cones and determine which is stronger, but the mechanism is unknown black arrow.

In this illustration, the right-hand process has more signal and becomes dominant. The cycle continues in a new direction. B Multipolar neurons extend and retract processes in various directions from the cell soma. At any given time one process is dominant, recruits the centrosome, and directs movement. Other processes can take over, presumably based on relative stabilization of growth cones by short-range and long-range signals.

It is unclear how the signal strengths at different growth cones are compared black arrow. C, i Radially migrating neurons undergoing locomotion along radial glia have a simple, relatively unbranched leading process. Branching may be suppressed by long-range signaling from receptors at the tip of the leading process black arrow. D The leading process in neurons undergoing somal translocation is anchored to the cells or extracellular matrix at the pia. Branching is also suppressed, perhaps by unidentified long-range inhibitory signals black arrow.

Question marks represent unknown mechanisms. Similar principles may apply to cortical projection neurons CPNs in the intermediate zone of the developing neocortex. These cells are multipolar, extending and retracting unstable processes as they thread their way between tangentially aligned axons and radially aligned glial fibers. The cells change direction frequently, one process then another taking the leading role Nadarajah et al. The growth cones on individual processes may detect short-range or long-range signals and be differentially stabilized, like the branched processes of CINs Fig.

Cytoskeletal forces may then pull the centrosome to the base of the dominant process, thereby steering the nucleus and selecting the direction for migration. When a multipolar CPN nears the top of the intermediate zone, a radially oriented process becomes dominant, and the CPN migrates radially Sakakibara et al. The CPN then migrates by locomotion, with the leading process entwined around radial glia Rakic, The cells are called bipolar, although there is only one leading process and the trailing process is actually the axon, growing from the rear.

The leading process is relatively unbranched and its tip moves forward continuously, without collapsing Nadarajah et al.

The leading process may help create a passage between the radial glia fiber and surrounding differentiating neurons. The base of the leading process, near the cell body, provides adhesion sites for moving the nucleus. Adhesion is discussed at the end of the review.

The locomotion phase ends when the leading process nears the pia and the cell body reaches a dense layer of immature neurons called the primitive cortical zone Nadarajah et al.

The tip seems to anchor to the pia and the nucleus migrates smoothly up the leading process, penetrating the primitive cortical zone. Somal translocation is also the main mechanism of CPN movement early in cortical development, when the intermediate zone has not developed, and there are no multipolar or locomotion phases. Instead, the new neuron inherits a long basal process from its radial glia progenitor Miyata et al. The pial process is under tension Miyata and Ogawa, The newborn neuron down-regulates apical junctions in the ventricular zone and the cell smoothly moves upward by somal translocation.

The role of the leading process therefore changes several times as CPNs journey from the ventricle to the marginal zone. In the intermediate zone there are multiple unstable processes, with the cell following whichever process is dominant at a particular time. Then, a single, stable leading process leads the way up the radial glia, and subsequently provides an attachment site during somal translocation.

Single, unbranched processes are presumably stabilized by adhesion or secreted factors that stimulate actin dynamics and delivery of new membrane, as described for growth cones Vitriol and Zheng, These inputs may also suppress branching Fig.

Indeed, branching is stimulated by mutations that reduce adhesion Fig. This suggests that adhesive signals from the process tip may inhibit branching along the shaft Fig. Similarly, anchoring of the tip of the leading process to the pia during somal translocation may suppress side branches Fig.

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Our laboratory has developed an in vitro model system in which glial-guided neuronal migration can be observed in real time. Cerebellar granule neurons migrate on astroglial fibers by apposing their cell soma against the glial arm, forming a specialized migration junction, and extending a motile leading process in the direction of migration. In vitro assays indicate that the neuronal antigen astrotactin functions as a neuron-glia ligand, and is likely to play a role in the movement of neurons along glial fibers. In heterotypic recombinations of neurons and glia from mouse cerebellum and rat hippocampus, neurons migrate on heterotypic glial processes with a cytology, speed and mode of movement identical to that of neuronal migration on homotypic glial fibers, suggesting that glial fibers provide a permissive pathway for neuronal migration in developing brain. In vivo analyses of developing cerebellum demonstrate a close coordination of afferent axon ingrowth relative to target cell migration. These studies indicate that climbing fibers contact immature Purkinje neurons during the migration and settling of Purkinje cells, implicating a role for afferents in the termination of migration.

Cellular Migration and Formation of Neuronal Connections

The genetic, molecular, and cellular mechanisms of neural development are essential for understanding evolution and disorders of neural systems. Recent advances in genetic, molecular, and cell biological methods have generated a massive increase in new information, but there is a paucity of comprehensive and up-to-date syntheses, references, and historical perspectives on this important subject. The Comprehensive Developmental Neuroscience series is designed to fill this gap, offering the most thorough coverage of this field on the market today and addressing all aspects of how the nervous system and its components develop. Each volume in the series consists of review style articles that average pp and feature numerous illustrations and full references. Series offers articles for full color pages addressing ways in which the nervous system and its components develop Features leading experts in various subfields as Section Editors and article Authors All articles peer reviewed by Section Editors to ensure accuracy, thoroughness, and scholarship Volume 2 sections include coverage of mechanisms which regulate: the formation of axons and dendrites, cell migration, synapse formation and maintenance during development, and neural activity, from cell-intrinsic maturation to early correlated patterns of activity.

The genetic, molecular, and cellular mechanisms of neural development are essential for understanding evolution and disorders of neural systems. Recent advances in genetic, molecular, and cell biological methods have generated a massive increase in new information, but there is a paucity of comprehensive and up-to-date syntheses, references, and historical perspectives on this important subject. The Comprehensive Developmental Neuroscience series is designed to fill this gap, offering the most thorough coverage of this field on the market today and addressing all aspects of how the nervous system and its components develop. Each volume in the series consists of review style articles that average pp and feature numerous illustrations and full references. Features leading experts in various subfields as Section Editors and article Authors.

Cell Reports. Molecular Psychiatry.

Acknowledgments

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.

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