Synaptic vesicle release regulates pre-myelinating oligodendrocyte-axon interactions in a neuron subtype-specific manner.

Oligodendrocyte-lineage cells are central nervous system (CNS) glia that perform multiple functions including the selective myelination of some but not all axons. During myelination, synaptic vesicle release from axons promotes sheath stabilization and growth on a subset of neuron subtypes. In comparison, it is unknown if pre-myelinating oligodendrocyte process extensions selectively interact with specific neural circuits or axon subtypes, and whether the formation and stabilization of these neuron-glia interactions involves synaptic vesicle release.

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Evolutionary Origins of the Oligodendrocyte Cell Type and Adaptive Myelination.

Oligodendrocytes are multifunctional central nervous system (CNS) glia that are essential for neural function in gnathostomes. The evolutionary origins and specializations of the oligodendrocyte cell type are among the many remaining mysteries in glial biology and neuroscience. The role of oligodendrocytes as CNS myelinating glia is well established, but recent studies demonstrate that oligodendrocytes also participate in several myelin-independent aspects of CNS development, function, and maintenance.

Identification of 3' UTR motifs required for mRNA localization to myelin sheaths in vivo.

Myelin is a specialized membrane produced by oligodendrocytes that insulates and supports axons. Oligodendrocytes extend numerous cellular processes, as projections of the plasma membrane, and simultaneously wrap multiple layers of myelin membrane around target axons. Notably, myelin sheaths originating from the same oligodendrocyte are variable in size, suggesting local mechanisms regulate myelin sheath growth.

Individual neuronal subtypes control initial myelin sheath growth and stabilization.

Background: In the developing central nervous system, pre-myelinating oligodendrocytes sample candidate nerve axons by extending and retracting process extensions. Some contacts stabilize, leading to the initiation of axon wrapping, nascent myelin sheath formation, concentric wrapping and sheath elongation, and sheath stabilization or pruning by oligodendrocytes. Although axonal signals influence the overall process of myelination, the precise oligodendrocyte behaviors that require signaling from axons are not completely understood.

Sequential specification of oligodendrocyte lineage cells by distinct levels of Hedgehog and Notch signaling.

During development of the central nervous system oligodendrocyte precursor cells (OPCs) give rise to both myelinating oligodendrocytes and NG2 glia, which are the most proliferative cells in the adult mammalian brain. NG2 glia retain characteristics of OPCs, and some NG2 glia produce oligodendrocytes, but many others persist throughout adulthood. Why some OPCs differentiate as oligodendrocytes during development whereas others persist as OPCs and acquire characteristics of NG2 glia is not known.

Development of an Embryonic Zebrafish Oligodendrocyte-Neuron Mixed Coculture System.

During vertebrate neural development, oligodendrocytes insulate nerve axons with myelin sheaths. Zebrafish (Danio rerio) has emerged as a useful model organism for studying oligodendrocyte development. However, the absence of an in vitro culture system necessitates in vivo manipulations and analyses, which, in some instances, limits the questions that can be addressed.

Neuronal activity biases axon selection for myelination in vivo.

An essential feature of vertebrate neural development is ensheathment of axons with myelin, an insulating membrane formed by oligodendrocytes. Not all axons are myelinated, but mechanisms directing myelination of specific axons are unknown. Using zebrafish, we found that activity-dependent secretion stabilized myelin sheath formation on select axons.

Mutation of 3-hydroxy-3-methylglutaryl CoA synthase I reveals requirements for isoprenoid and cholesterol synthesis in oligodendrocyte migration arrest, axon wrapping, and myelin gene expression.

Myelin membrane, which ensheaths axons, has an unusually high amount of cholesterol. Cholesterol influences membrane fluidity and assembles lipid-rich microdomains within membranes, and some studies have shown that cholesterol is important for myelination. How cholesterol influences the development and differentiation of oligodendrocytes, glial cells that make myelin, is not known nor is clear whether isoprenoids, which also are products of the cholesterol biosynthetic pathway, contribute to myelination.

Single vesicle imaging indicates distinct modes of rapid membrane retrieval during nerve growth.

Background: During nerve growth, cytoplasmic vesicles add new membrane preferentially to the growth cone located at the distal tip of extending axons. Growth cone membrane is also retrieved locally, and asymmetric retrieval facilitates membrane remodeling during growth cone repulsion by a chemorepellent gradient. Moreover, growth inhibitory factors can stimulate bulk membrane retrieval and induce growth cone collapse.

Bidirectional remodeling of β1-integrin adhesions during chemotropic regulation of nerve growth.

Background: Chemotropic factors in the extracellular microenvironment guide nerve growth by acting on the growth cone located at the tip of extending axons. Growth cone extension requires the coordination of cytoskeleton-dependent membrane protrusion and dynamic adhesion to the extracellular matrix, yet how chemotropic factors regulate these events remains an outstanding question. We demonstrated previously that the inhibitory factor myelin-associated glycoprotein (MAG) triggers endocytic removal of the adhesion receptor β1-integrin from the growth cone surface membrane to negatively remodel substrate adhesions during chemorepulsion.

Second messengers and membrane trafficking direct and organize growth cone steering.

Graded distributions of extracellular cues guide developing axons toward their targets. A network of second messengers - Ca(2+) and cyclic nucleotides - shapes cue-derived information into either attractive or repulsive signals that steer growth cones bidirectionally. Emerging evidence suggests that such guidance signals create a localized imbalance between exocytosis and endocytosis, which in turn redirects membrane, adhesion and cytoskeletal components asymmetrically across the growth cone to bias the direction of axon extension.

Asymmetric endocytosis and remodeling of beta1-integrin adhesions during growth cone chemorepulsion by MAG.

Gradients of chemorepellent factors released from myelin may impair axon pathfinding and neuroregeneration after injury. We found that, analogously to the process of chemotaxis in invasive tumor cells, axonal growth cones of Xenopus spinal neurons modulate the functional distribution of integrin receptors during chemorepulsion induced by myelin-associated glycoprotein (MAG). A focal MAG gradient induced polarized endocytosis and concomitant asymmetric loss of beta(1)-integrin and vinculin-containing adhesions on the repellent side during repulsive turning.

Identification of potential protein interactors of Lrrk2.

Pathogenic substitutions in the Lrrk2 protein have been shown to be an important cause of both familial and sporadic parkinsonism. The molecular pathway involved in Lrrk2 dopaminergic neuron degeneration remains elusive. Employing a combination of Lrrk2-mediated protein precipitation and tandem mass spectrometry, we identified 14 potential Lrrk2 binding partners.