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Enhancing repair of myelin is an important but still elusive therapeutic goal in many neurological disorders (1). In multiple sclerosis, an inflammatory demyelinating disease, endogenous remyelination does occur but is frequently insufficient to restore function. Both parenchymal oligodendrocyte progenitor cells and endogenous adult neural stem cells resident within the subventricular zone are known sources of remyelinating cells (2). Here we characterize the contribution to remyelination of a subset of adult neural stem cells, identified by their expression of Gli1, a transcriptional effector of the sonic hedgehog pathway. We show that these cells are recruited from the subventricular zone to populate demyelinated lesions in the forebrain but never enter healthy, white matter tracts. Unexpectedly, recruitment of this pool of neural stem cells, and their differentiation into oligodendrocytes, is significantly enhanced by genetic or pharmacological inhibition of Gli1. Importantly, complete inhibition of canonical hedgehog signalling was ineffective, indicating that the role of Gli1 both in augmenting hedgehog signalling and in retarding myelination is specialized. Indeed, inhibition of Gli1 improves the functional outcome in a relapsing/remitting model of experimental autoimmune encephalomyelitis and is neuroprotective. Thus, endogenous neural stem cells can be mobilized for the repair of demyelinated lesions by inhibiting Gli1, identifying a new therapeutic avenue for the treatment of demyelinating disorders., Remyelination in the adult human and mouse brains is performed by two cell types: oligodendrocyte progenitor cells (OPCs) and neural stem cells (NSCs). OPCs, which are present in the parenchyma [...]

Peripheral nerves are organized into discrete compartments. Axons, Schwann cells (SCs), and endoneurial fibroblasts (EFs) reside within the endoneurium and are surrounded by the perineurium, a cellular sheath comprised of layers of perineurial glia (PNG). SC secretion of Desert Hedgehog (Dhh) regulates this organization. In Dhh nulls, the perineurium is deficient and the endoneurium is subdivided into small compartments termed minifascicles. Human Dhh mutations cause a neuropathy with similar defects. Here we examine the role of Gli1, a canonical transcriptional effector of hedgehog signaling, in regulating peripheral nerve organization in mice of both genders. We identify PNG, EFs, and pericytes as Gli1-expressing cells by genetic fate mapping. Although expression of Dhh by SCs and Gli1 in target cells is coordinately regulated with myelination, Gli1 expression unexpectedly persists in Dhh null EFs. Thus, Gli1 is expressed in EFs noncanonically (i.e., independent of hedgehog signaling). Gli1 and Dhh also have nonredundant activities. Unlike Dhh nulls, Gli1 nulls have a normal perineurium. Like Dhh nulls, Gli1 nulls form minifascicles, which we show likely arise from EFs. Thus, Dhh and Gli1 are independent signals: Gli1 is dispensable for perineurial development but functions cooperatively with Dhh to drive normal endoneurial development. During development, Gli1 also regulates endoneurial extracellular matrix production, nerve vascular organization, and has modest, nonautonomous effects on SC sorting and myelination of axons. Finally, in adult nerves, induced deletion of Gli1 is sufficient to drive minifascicle formation. Thus, Gli1 regulates the development and is required to maintain the endoneurial architecture of peripheral nerves. [ABSTRACT FROM AUTHOR]

Sodium channel subtypes are frequently coexpressed within neurons. Recent studies demonstrate that targeting of specific channel subtypes to distinct membrane domains of axons is regulated by local signals from myelinating gila; they also show that channel subtypes are sequentially expressed at nodes of Ranvier, indicating an unexpected regulation in the composition of these domains.

The peripheral nerve predilection of Mycobacterium leprae, responsible for leprosy, has been studied with attention to the role of the cell wall phenolic glycolipid-1. Evidence for the involvement of the specific trisaccharide unit of the phenolic glycolipid-1 (PGL-1) predilection is offered. PGL-1 binds to the native laminin-2 in the basal lamina of Schwann cell-axon units specifically.

The role of sialic acid-binding epitope of myelin-associated glycoprotein (MAG) on neurite outgrowth was demonstrated through site-directed mutagenesis. Results show that the neurite inhibitory activity of MAG is distinct from its sialic acid site since by itself, sialic acid binding is not sufficient to effect inhibition of axonal growth. MAG's sialic acid-dependent binding is lost when it is mutated to either aspartic acid or alanine. Meanwhile MAG retains its ability to inhibit axonal regeneration when it is expressed at the surface of either Schwann or Chinese hamster ovary cells.