A requisite component of nervous system development is the achievement of cellular recognition and spatial segregation through competition-based refinement mechanisms. Competition for available axon space by myelinating oligodendrocytes ensures that all relevant CNS axons are myelinated properly. To ascertain the nature of this competition, we generated a transgenic mouse with sparsely labeled oligodendrocytes and establish that individual oligodendrocytes occupying similar axon tracts can greatly vary the number and lengths of their myelin internodes. Here we show that intercellular interactions between competing oligodendroglia influence the number and length of myelin internodes, referred to as myelinogenic potential, and identify the amino-terminal region of Nogo-A, expressed by oligodendroglia, as necessary and sufficient to inhibit this process. Exuberant and expansive myelination/ remyelination is detected in the absence of Nogo during development and after demyelination, suggesting that spatial segregation and myelin extent is limited by microenvironmental inhibition. We demonstrate a unique physiological role for Nogo-A in the precise myelination of the developing CNS. Maximizing the myelinogenic potential of oligodendrocytes may offer an effective strategy for repair in future therapies for demyelination.T he spatial alignment of myelin internodes along axons facilitates the process of saltatory conduction, maximizing the speed and efficacy of action potential propagation throughout the nervous system. In the CNS, myelin is formed by oligodendrocytes, cells with the capacity to form multiple myelin internodes (1). What developmental mechanisms control the generation and coordination of the precise number and length of myelin internodes? Though recent studies have revealed extrinsic cues and transcriptional and epigenetic determinants that regulate oligodendrocyte differentiation (2-7), achievement of the precise spatial organization of myelin internodes necessitates a mechanism whereby neighboring oligodendroglial cells coordinate the appropriate number of myelin internodes generated. This coordination could be achieved through oligodendroglial competition for inductive cues and/or available axonal space (8). Variations in the number and length of myelin internodes formed by individual oligodendrocytes support the likelihood of environmental regulation of myelination. However, providing evidence of this variation requires a strategy that facilitates the resolution and analysis of individual myelinating oligodendrocytes in vivo. Results Individual Oligodendrocytes Exhibit Great Variability in the Numberand Lengths of Myelin Internodes Throughout the CNS. Though the heterogeneity of oligodendrocyte morphology has been recognized for the past century (9, 10), efforts to accurately examine oligodendrocytes have been hindered by the high density of myelinating cells, limiting the ability to confidently attribute specific myelin internodes to any particular oligodendrocyte. Existing methods approximate the n...

The development of the nervous system involves the generation of a stunningly diverse array of neuronal subtypes that enable complex information processing and behavioral outputs. Deciphering how the nervous system acquires and interprets information and orchestrates behaviors will be greatly enhanced by the identification of distinct neuronal circuits and by an understanding of how these circuits are formed, changed, and/or maintained over time. Addressing these challenging questions depends in part on the ability to accurately identify and characterize the unique neuronal subtypes that comprise individual circuits. Distinguishing characteristics of neuronal subgroups include but are not limited to neurotransmitter phenotype, dendritic morphology, the identity of synaptic partners, and the expression of constellations of subgroup-specific proteins, including ion channel subtypes.

The oligodendrocyte precursor cell (OPC) arises from the subventricular zone (SVZ) during early vertebrate development to migrate and proliferate along axon tracts before differentiating into the myelin-forming oligodendrocyte. We demonstrate that the spatial and temporal regulation of oligodendrocyte differentiation depends intimately on the axonal microenvironment and the density of precursor cells along a specified axonal area. Differentiation does not require dynamic axonal signaling, but instead is induced by packing constraints resulting from intercellular interactions. Schwann cells and even artificial beads bound to the axonal surface can mimic these constraints and promote differentiation. Together, these results describe the coordinately controlled biophysical interaction of oligodendrocyte precursors within an axonal niche leading to self-renewal and differentiation.myelination ͉ neuronal-glial interactions ͉ mechanotransduction D amage to the myelin membrane, as a result of nerve injury or disease, significantly impairs the ability of the nervous system to communicate and can lead to a host of debilitating symptoms, as well as an ultimate loss of function. In the CNS, demyelination is accompanied by the loss of oligodendrocytes, the terminally differentiated cells responsible for the formation of the myelin sheath. After the initial onset of demyelination, OPCs are induced to differentiate and remyelinate, effectively replacing lost oligodendrocytes. Unfortunately, the capacity for remyelination is limited, and ultimately fails in the presence of chronic demyelination. It remains unclear why the CNS cannot sustain this initial ability to repair the myelin sheath. One possible explanation is that adult OPCs eventually lose their ability to differentiate into remyelinating oligodendrocytes (1). It is plausible that the continuous presence of a demyelinating environment is responsible for inhibiting the differentiation process. If this supposition is true, then it is imperative to identify the environmental conditions conducive to the ongoing production of oligodendrocytes.Examining oligodendrocyte generation during development could prove useful for determining the role of the environment in the induction of differentiation. Developing OPCs are proliferative and self-renewing cells that originate in the SVZ and migrate along axons throughout the CNS. During development, an OPC must decide how many times it will divide, and where it will migrate. Also, an OPC must choose whether to remain as a precursor cell into adulthood or to differentiate into a myelinating oligodendrocyte. Such complex decisions are likely to be heavily influenced by the nature of the surrounding environment and by the behavior of neighboring cells. Based on these assumptions, it is our goal to identify the environmental factors that influence the decision of an OPC to differentiate into an oligodendrocyte. To accomplish this goal, we first looked at the developing rat spinal cord to examine the temporal regulation of oligodendrocy...

Neurons and glia share a mutual dependence in establishing a functional relationship, and none is more evident than the process by which axons control myelination. Here, we identify LRR and Ig domain-containing, Nogo receptor-interacting protein (LINGO-1) as a potent axonal inhibitor of oligodendrocyte differentiation and myelination that is regulated by nerve growth factor and its cognate receptor TrkA in a dose-dependent manner. Whereas LINGO-1 expressed by oligodendrocyte progenitor cells was previously identified as an inhibitor of differentiation, we demonstrate that axonal expression of LINGO-1 inhibits differentiation with equal potency. Disruption of LINGO-1 on either cell type is sufficient to overcome the inhibitory action and promote differentiation and myelination, independent of axon diameter. Furthermore, these results were recapitulated in transgenic mice overexpressing the full length LINGO-1 under the neuronal promoter synapsin. Myelination was greatly inhibited in the presence of enforced axonal LINGO-1. The implications of these results relate specifically to the development of potential therapeutics targeting extrinsic growth factors that may regulate the axonal expression of modulators of oligodendrocyte development.

The formation of myelin is dependent on a reciprocal and intimate relationship between neurons and the myelin-forming glia. Recently, the neurotrophin family of growth factors has been shown to regulate the complex cell-cell interactions that control myelination. Neurotrophins and their receptors influence myelin formation via two distinct mechanisms, either by acting on the neurons, changing the axonal signals that control myelination, or by acting directly on the myelin-forming glia. In this review, we will discuss research highlighting the ability of neurotrophins to both promote and inhibit the myelination process. As reflected in the work presented here, these effects are dependent on a delicate balance of which neurotrophins are expressed, and what receptors are activated. Additionally, we examine an emerging model in which the growth factors that promote the early survival and differentiation of particular sets of neurons later play important roles as key regulators in glial development. Characterizing the temporal expression and the cellular targets of neurotrophins, both during development and after injury, represents a pivotal step in developing a greater understanding of the myelination process, contributing to the development of effective treatments for demyelinating conditions. We conclude this review by discussing the potential for neurotrophins as therapeutics in the quest for remyelination.

Drowning is the number one cause of accidental death in children with Autism Spectrum Disorder (ASD). Few studies have examined the effectiveness of swim instruction for improving water safety skills in children with moderate to severe ASD. This study examines the feasibility and effectiveness of an aquatic therapy program on water safety and social skills in children with mild to severe ASD (n = 7). Water safety skills were evaluated using the Aquatics Skills Checklist and social skills were measured using the Social Skills Improvement Scale. We provide preliminary evidence that children with ASD can improve water safety skills (p = 0.0002), which are important for drowning prevention after only 8 h of intervention. However, social skills did not respond to intervention (p = 0.6409).

The development and maturation of an oligodendroglial cell is comprised of three intimately related processes that include proliferation, differentiation, and myelination. Here we review how proliferation and differentiation are controlled by distinct molecular mechanisms and discuss whether differentiation is merely a default of inhibited proliferation. We then address whether differentiation and myelination can be uncoupled in a similar manner. This task is particularly challenging because an oligodendrocyte cannot myelinate without first differentiating, and these processes are therefore not mutually exclusive. Is it solely the presence of the axon that distinguishes a differentiated oligodendrocyte from a myelinating one? Uncoupling these two processes requires identifying specific signals that regulate myelination without affecting the differentiation process. We will review current understanding of the relationship between differentiation and myelination and discuss whether these two processes can truly be uncoupled.

By using outcome data at the time of admission, a discharge destination can be predicted for stroke patients with significant sensitivity and specificity.