NGF Controls Axonal Receptivity to Myelination by Schwann Cells or Oligodendrocytes

191

188

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...

Section: Methodsmentioning

confidence: 99%

“…OPC-DRG cocultures were prepared as described previously (2). Briefly, DRG neurons from E13-15 Sprague-Dawley rats were dissociated, plated, and purified on collagen-coated coverslips in the presence of NGF (100 ng/ml).…”

Section: Methodsmentioning

confidence: 99%

The geometric and spatial constraints of the microenvironment induce oligodendrocyte differentiation

Rosenberg

Kelland

Tokar

et al. 2008

191

188

“…The in vitro myelinating coculture represents a reduced system that is ideal for manipulating the microenvironment (15). Similar to oligodendroglial development in vivo, oligodendrocyte precursor cells (OPCs) cocultured with purified sensory neurons undergo an initial period of proliferation in response to axonal cues (15,16) before differentiating into myelinating oligodendrocytes.…”

Section: Individual Oligodendrocytes Exhibit Great Variability In Thementioning

confidence: 99%

Neurite outgrowth inhibitor Nogo-A establishes spatial segregation and extent of oligodendrocyte myelination

Chong

Rosenberg

Fancy

et al. 2011

196

205

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...

“…In vitro study have indicated that NGF promotes myelination in Schwann cells and inhibits conversion of premyelinating into myelinating oligodendrocyte in a cellular system derived from embryonic dorsal root ganglia (53). However, it is unknown whether the same observations are applicable to remyelination after injury.…”

Section: Cns Inflammation and The Cholinergic System Of The Basal Formentioning

confidence: 99%

Cognitive deficit associated with cholinergic and nerve growth factor down-regulation in experimental allergic encephalomyelitis in rats

D’Intino

Paradisi

Fernández

et al. 2005

Clinical symptoms in multiple sclerosis include cognitive dysfunction. Difficulties in learning and remembering new information represent the most common cognitive deficit and are associated with a general and progressive brain pathology. Possible pathogenetic mechanisms for neuronal damage such as neuroprotective strategies are under active investigation also in experimental allergic encephalomyelitis, the most widely used experimental model for multiple sclerosis. In this paper we demonstrate that a selective deficit in learning and memory performance, as investigated by the Morris water maze test, is a consistent feature in rat encephalomyelitis, which correlates with a decline in choline acetyltransferase activity and nerve growth factor mRNA level in cerebral cortex, hippocampus, and basal forebrain. Treatment aimed to restore acetylcholine content through chronic administration of selective acetylcholinesterase inhibitors (rivastigmine and donepezil) restores cognitive performance, choline acetyltransferase activity, and nerve growth factor mRNA expression.choline acetyltransferase ͉ multiple sclerosis ͉ learning and memory ͉ water maze ͉ acetylcholinesterase inhibitors