Mechanisms of glial-guided neuronal migration in vitro and in vivo

Summary 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.     

Extracellular matrix and neuronal movement

Summary During brain development, both neuronal migration and axon guidance are influenced by extracellular matrix molecules present in the environment of the migrating neuronal cell bodies and nerve fibers. Glial laminin is an extracellular matrix protein which these early brain cells preferentially attach to. Extracellular glycosaminoglycans are suggested to function in restricting neuronal cell bodies and axons from certain brain areas. Since laminin is deposited along the radial glial fibers and along the developing nerve pathways in punctate form, the punctate assemblies may be one of the key factors in routing the developing neurons in vivo. This review discusses the role of laminin in neuronal movement given the present concept of the extracellular matrix molecules and their proposed interactions.     

Extracellular matrix and neuronal movement

During brain development, both neuronal migration and axon guidance are influenced by extracellular matrix molecules present in the environment of the migrating neuronal cell bodies and nerve fibers. Glial laminin is an extracellular matrix protein which these early brain cells preferentially attach to. Extracellular glycosaminoglycans are suggested to function in restricting neuronal cell bodies and axons from certain brain areas. Since laminin is deposited along the radial glial fibers and along the developing nerve pathways in punctate form, the punctate assemblies may be one of the key factors in routing the developing neurons in vivo. This review discusses the role of laminin in neuronal movement given the present concept of the extracellular matrix molecules and their proposed interactions.     

Nitric oxide stimulates human neural progenitor cell migration via cGMP-mediated signal transduction

Neuronal migration is one of the most critical processes during early brain development. The gaseous messenger nitric oxide (NO) has been shown to modulate neuronal and glial migration in various experimental models. Here, we analyze a potential role for NO signaling in the migration of fetal human neural progenitor cells. Cells migrate out of cultured neurospheres and differentiate into both neuronal and glial cells. The neurosphere cultures express neuronal nitric oxide synthase and soluble guanylyl cyclase that produces cGMP upon activation with NO. By employing small bioactive enzyme activators and inhibitors in both gain and loss of function experiments, we show NO/cGMP signaling as a positive regulator of migration in neurosphere cultures of early developing human brain cells. Since NO signaling regulates cell movements from developing insects to mammalian nervous systems, this transduction pathway may have evolutionary conserved functions.     

Cell lineage and cell migration in the developing cerebral cortex

Summary Modern techniques which trace lineages of individual progenitor cells have provided some clues about the processes that determine cell fate in the brain, and have also given us some information about migratory patterns of clonally related cells. In many parts of the central nervous system, progenitors are multipotent; single clones can contain multiple neuronal types or even mixtures of neurons and glia. In addition, one can observe a wide distribution in clone size, even when marking is done in a narrow time window. This suggests that progenitor cells may be fairly plastic and responsive to environmental signals. In the developing cortex, clonally related cells are initially grouped near each other, as in the retina and tectum. However, the subsequent migration of these cells from the ventricular zone to the cortex along glial fibers is accompanied by a progressive dispersion of clonally related neurons.     

Iron deposits in the chronically inflamed central nervous system and contributes to neurodegeneration

Neurodegenerative disorders are characterized by the presence of inflammation in areas with neuronal cell death and a regional increase in iron that exceeds what occurs during normal aging. The inflammatory process accompanying the neuronal degeneration involves glial cells of the central nervous system (CNS) and monocytes of the circulation that migrate into the CNS while transforming into phagocytic macrophages. This review outlines the possible mechanisms responsible for deposition of iron in neurodegenerative disorders with a main emphasis on how iron-containing monocytes may migrate into the CNS, transform into macrophages, and die out subsequently to their phagocytosis of damaged and dying neuronal cells. The dying macrophages may in turn release their iron, which enters the pool of labile iron to catalytically promote formation of free-radical-mediated stress and oxidative damage to adjacent cells, including neurons. Healthy neurons may also chronically acquire iron from the extracellular space as another principle mechanism for oxidative stress-mediated damage. Pharmacological handling of monocyte migration into the CNS combined with chelators that neutralize the effects of extracellular iron occurring due to the release from dying macrophages as well as intraneuronal chelation may denote good possibilities for reducing the deleterious consequences of iron deposition in the CNS.     

Neuronal growth cone migration

The neuronal growth cone is a semi-autonomous portion of the developing neuron that is highly specialized for motile activity. Migrating neurons may share some features with neuronal growth cones. I review some of what has been learned about growth cone initiation, the differentiation of axons and dendrites, the role of the cytoskeleton in motility, the movements of membrane vesicles, the factors regulating the rate and direction of growth cone movement, and the further differentiation of growth cones as they enter the target area and initiate synaptogenesis. Where appropriate, I draw comparisons to what is known about the migration of neurons.     

Neuronal growth cone migration

Summary The neuronal growth cone is a semi-autonomous portion of the developing neuron that is highly specialized for motile activity. Migrating neurons may share some features with neuronal growth cones. I review some of what has been learned about growth cone initiation, the differentiation of axons and dendrites, the role of the cytoskeleton in motility, the movements of membrane vesicles, the factors regulating the rate and direction of growth cone movement, and the further differentiation of growth cones as they enter the target area and initiate synaptogenesis. Where appropriate, I draw comparisons to what is known about the migration of neurons.     

Reelin-Disabled-1 signaling in neuronal migration: splicing takes the stage

Reelin-Disabled-1 (Dab1) signaling has a well-established role in regulating neuronal migration during brain development. Binding of Reelin to its receptors induces Dab1 tyrosine phosphorylation. Tyrosine-phosphorylated Dab1 recruits a wide range of SH2 domain-containing proteins and activates multiple signaling cascades, resulting in cytoskeleton remodeling and precise neuronal positioning. In this review, we summarize recent progress in the Reelin-Dab1 signaling field. We focus on Dab1 alternative splicing as a mechanism for modulating the Reelin signal in developing brain. We suggest that correct positioning of neurons in the developing brain is at least partly controlled by alternatively-spliced Dab1 isoforms that differ in the number and type of tyrosine phosphorylation motifs that they contain. We propose a model whereby different subsets of SH2 domain-containing proteins are activated by different Dab1 isoforms, resulting in coordinated migration of neurons.     

The right neuron at the wrong place: biology of heterotopic neurons in cortical neuronal migration disorders, with special reference to associated pathologies

During the development of the neocortex, neurogenesis and neuronal differentiation occur in two separate locations. Thus neurons have to migrate through the future white matter. Arrested or excessive migration leads neurons to differentiate in a heterotopic position. Such neuronal migration disorders (NMDs) occur sporadically in normal development but are markedly increased as a consequence of genetic defects or after exposure to toxic drugs during the period of migration. Anatomofunctional studies in rodents with NMDs have revealed that heterotopic neurons form essentially normal afferent and efferentconnections, which has been interpreted as evidence that the connectionpattern of cortical neurons is specified prior to migration. In addition, recent data show that heterotopic neurons can be contacted by environmental, that is local, fibres that normally never innervate the neocortex. This dual connectivity leads heterotopias to form bridges between their environmental and original network. Such an abnormal pattern of connectivity could contribute to the pathophysiology of disorders associated with NMDs such as epilepsy. Received 16 December 1998; received after revision 5 February 1999; accepted 9 February 1999     

In vitro neurogenesis: development and functional implications of iPSC technology

Neurogenesis is the developmental process regulating cell proliferation of neural stem cells, determining their differentiation into glial and neuronal cells, and orchestrating their organization into finely regulated functional networks. Can this complex process be recapitulated in vitro using induced pluripotent stem cell (iPSC) technology? Can neurodevelopmental and neurodegenerative diseases be modeled using iPSCs? What is the potential of iPSC technology in neurobiology? What are the recent advances in the field of neurological diseases? Since the applications of iPSCs in neurobiology are based on the capacity to regulate in vitro differentiation of human iPSCs into different neuronal subtypes and glial cells, and the possibility of obtaining iPSC-derived neurons and glial cells is based on and hindered by our poor understanding of human embryonic development, we reviewed current knowledge on in vitro neural differentiation from a developmental and cellular biology perspective. We highlight the importance to further advance our understanding on the mechanisms controlling in vivo neurogenesis in order to efficiently guide neurogenesis in vitro for cell modeling and therapeutical applications of iPSCs technology.     

Netrins and netrin receptorsRID="†"ID="†" Review

The formation of precise connections between neurons and their targets during development is dependent on extracellular guidance cues that allow growing axons to navigate to their targets. One family of such guidance molecules. conserved across all species examined, is that of the netrin/UNC-6 proteins. Netrins act to both attract and repel the growing axons of a broad range of neuronal cell types during development and are also involved in controling neuronal cell migration. These actions are mediated by specific receptor complexes containing either the colorectal cancer (DCC) or neogenin protein, in the case of the attractive receptor, or UNC-5-related proteins, in the case of the repellent receptor. Recent work has identified a key role for intracellular cyclic nucleotide levels in regulating the nature of the response of the growing axon to netrins as either attractive or repulsive. Netrin-DCC signaling has also been shown to regulate cell death in epithelial cells in vitro, raising the interesting possibility that netrins may also regulate cell death in the developing nervous system.     

The specification of neuronal identity in the mammalian cerebral cortex

The determination of neuronal fate in the developing cerebral cortex has been studied by tracking normal cell lineages in the cortex, and by testing the commitment of young cortical neurons to their normal fates. These studies together suggest that neuronal progenitors are multipotent during development and have the potential to produce neurons destined for many or all of the cortical layers. However, the laminar identity of an individual neuron appears to be specified through environmental interactions at the time of the cell's terminal mitotic division, prior to its migration into the cortical plate.     

The specification of neuronal identity in the mammalian cerebral cortex

Summary The determination of neuronal fate in the developing cerebral cortex has been studied by tracking normal cell lineages in the cortex, and by testing the commitment of young cortical neurons to their normal fates. These studies together suggest that neuronal progenitors are multipotent during development and have the potential to produce neurons destined for many or all of the cortical layers. However, the laminar identity of an individual neuron appears to be specified through environmental interactions at the time of the cell's temrinal mitotic division, prior to its migration into the cortical plate.     

Getting there and being there in the cerebral cortex

The mammalian neocortex is composed of functional areas that are specified to process particular aspects of information. How is this specification achieved during development? Since cells migrate to their final positions in the developing nervous system, a central issue is the relation between cellular migration and positional information. This review combines evidence for early positional specification in the developing cortex with evidence for cellular dispersion during migration. A model is suggested whereby stable cues provide positional information and minorities of ‘displaced’ cells are respecified accordingly. Comparison with other parts of the CNS reveals that cellular dispersal is ubiquitous and has to be included in any mechanism relaying positional specification. Ontogenetic and phylogenetic considerations suggest that radial glial cells might provide the positional information in the developing nervous system.     

Mechanisms of endothelial cell migration

Cell migration plays a central role in a variety of physiological and pathological processes during our whole life. Cellular movement is a complex, tightly regulated multistep process. Although the principle mechanisms of migration follow a defined general motility cycle, the cell type and the context of moving influences the detailed mode of migration. Endothelial cells migrate during vasculogenesis and angiogenesis but also in a damaged vessel to restore vessel integrity. Depending on the situation they migrate individually, in chains or sheets and complex signaling, intercellular signals as well as environmental cues modulate the process. Here, the different modes of cell migration, the peculiarities of endothelial cell migration and specific guidance molecules controlling this process will be reviewed.     

VEGF ligands and receptors: implications in neurodevelopment and neurodegeneration

Intensive research in the last decade shows that the prototypic angiogenic factor vascular endothelial growth factor (VEGF) can have direct effects in neurons and modulate processes such as neuronal migration, axon outgrowth, axon guidance and neuronal survival. Depending on the neuronal cell type and the process, VEGF seems to exert these effects by signaling via different receptors. It is also becoming clear that other VEGF ligands such as VEGF-B, -C and -D can act in various neuronal cell types as well. Moreover, apart from playing a role in physiological conditions, VEGF and VEGF-B have been related to different neurological disorders. We give an update on how VEGF controls different processes during neurodevelopment as well as on its role in several neurodegenerative disorders. We also discuss recent findings demonstrating that other VEGF ligands influence processes such as neurogenesis and dendrite arborization and participate in neurodegeneration.     

Recent advances in cerebellar granule cell migration

In the developing brain, postmitotic neurons exhibit dynamic changes in mode, direction, tempo and rate of migration as they traverse different cortical layers. Such changes in cell migration require orchestrated activities of multiple guidance cues and transmembrane signals. In this article, we first describe when, where and how cerebellar granule cells alter their migratory behavior during the entire course of their migration. We then present how internal (inherent) programs regulate the sequential changes in the migratory behavior of granule cells in vitro. Finally, we discuss the roles of external guidance cues and transmembrane signals in controlling granule cell migration.     

Synapse elimination in the developing cerebellum

Neural circuits in neonatal animals contain numerous redundant synapses that are functionally immature. During the postnatal period, unnecessary synapses are eliminated while functionally important synapses become stronger and mature. The climbing fiber (CF) to the Purkinje cell (PC) synapse is a representative model for the analysis of postnatal refinement of neuronal circuits in the central nervous system. PCs are initially innervated by multiple CFs with similar strengths around postnatal day 3 (P3). Only a single CF is selectively strengthened during P3–P7 (functional differentiation), and the strengthened CF undergoes translocation from soma to dendrites of PCs from P9 on (dendritic translocation). Following the functional differentiation, supernumerary CF synapses on the soma are eliminated, which proceeds in two distinct phases: the early phase from P7 to around P11 and the late phase from around P12 to P17. Here, we review our current understanding of cellular and molecular mechanisms of CF synapse elimination in the developing cerebellum.     

Mechanism of neurogenesis in adult avian brain

Summary Adult neurogenesis in birds offers unique opportunities to study basic questions addressing the birth, migration and differentiation of neurons. Neurons in adult canaries originate from discrete proliferative regions on the walls of the lateral ventricles. They migrate away from their site of birth, initially at high rates, along the processes of radial cells. The rates of dispersal diminish as the young neurons invade regions devoid of radial fibers, probably under the guidance of other cues. The discrete sites of birth in the ventricular zone generate neurons that end up differentiating throughout the telencephelon. New neurons may become interneurons or projection neurons; the latter connect two song control nuclei between neostriatum and archistriatum. Radial cells, that in mammals disappear as neurogenesis comes to an end, persist in the adult avian brain. The presence of radial cells may be key to adult neurogenesis. Not only do they serve as guides for initial dispersal, they also divide and may be the progenitors of new neurons.