Unexpected Remyelination in the Absence of Matrix Metalloproteinase 7.

In multiple sclerosis (MS), an influx of immune cells into the central nervous system leads to focal demyelinating lesions in the brain, optic nerve, and spinal cord. As MS progresses, remyelination increasingly fails, leaving neuronal axons vulnerable to degeneration and resulting in permanent neurological disability. In chronic MS lesions, the aberrant accumulation of extracellular matrix (ECM) molecules, including fibronectin and hyaluronan, impairs oligodendrocyte progenitor cell differentiation, contributing to remyelination failure.

Dmd mdx mice have defective oligodendrogenesis, delayed myelin compaction and persistent hypomyelination.

Duchenne muscular dystrophy (DMD) is caused by mutations in the DMD gene, resulting in the loss of dystrophin, a large cytosolic protein that links the cytoskeleton to extracellular matrix receptors in skeletal muscle. Aside from progressive muscle damage, many patients with DMD also have neurological deficits of unknown etiology. To investigate potential mechanisms for DMD neurological deficits, we assessed postnatal oligodendrogenesis and myelination in the Dmdmdx mouse model.

The AMPK activator metformin improves recovery from demyelination by shifting oligodendrocyte bioenergetics and accelerating OPC differentiation.

Multiple Sclerosis (MS) is a chronic disease characterized by immune-mediated destruction of myelinating oligodendroglia in the central nervous system. Loss of myelin leads to neurological dysfunction and, if myelin repair fails, neurodegeneration of the denuded axons. Virtually all treatments for MS act by suppressing immune function, but do not alter myelin repair outcomes or long-term disability.

Current Insights Into Oligodendrocyte Metabolism and Its Power to Sculpt the Myelin Landscape.

Once believed to be part of the or "nerve glue" network in the central nervous system (CNS), oligodendroglial cells now have established roles in key neurological functions such as myelination, neuroprotection, and motor learning. More recently, oligodendroglia has become the subject of intense investigations aimed at understanding the contributions of its energetics to CNS physiology and pathology. In this review, we discuss the current understanding of oligodendroglial metabolism in regulating key stages of oligodendroglial development and health, its role in providing energy to neighboring cells such as neurons, as well as how alterations in oligodendroglial bioenergetics contribute to disease states.

Investigating demyelination, efficient remyelination and remyelination failure in organotypic cerebellar slice cultures: Workflow and practical tips.

Healthy myelin is essential for proper brain function. When the myelin sheath is damaged, fast saltatory impulse conduction is lost and neuronal axons become vulnerable to degeneration. Thus, regeneration of the myelin sheath by encouraging oligodendrocyte lineage cells to remyelinate the denuded axons is a promising therapeutic target for demyelinating diseases such as multiple sclerosis.

Brain Dysfunction in LAMA2-Related Congenital Muscular Dystrophy: Lessons From Human Case Reports and Mouse Models.

Laminin α2 gene (LAMA2)-related Congenital Muscular Dystrophy (CMD) was distinguished by a defining central nervous system (CNS) abnormality-aberrant white matter signals by MRI-when first described in the 1990s. In the past 25 years, researchers and clinicians have expanded our knowledge of brain involvement in LAMA2-related CMD, also known as Congenital Muscular Dystrophy Type 1A (MDC1A). Neurological changes in MDC1A can be structural, including lissencephaly and agyria, as well as functional, including epilepsy and intellectual disability.

Prefrontal cortex NG2 glia undergo a developmental switch in their responsiveness to exercise.

Aerobic exercise is known to influence brain function, e.g., enhancing executive function in both children and adults, with many of these influences being attributed to alterations in neurogenesis and neuronal function.

Distinct Requirements for Extracellular and Intracellular MMP12 in the Development of the Adult V-SVZ Neural Stem Cell Niche.

The regulatory mechanisms that control neural stem cell (NSC) activation in the adult ventricular-subventricular zone (V-SVZ) stem cell niche have been the focus of intense investigation, yet how the niche first develops and organizes is poorly understood. Here, we examined matrix metalloproteinases (MMPs) for potential roles in V-SVZ stem cell niche development. MMP12 was found to promote appropriate niche cellular arrangements, the formation of specialized niche extracellular matrix, and the translational planar cell polarity of ependymal cells that surround and support niche NSCs.

Conditional knockout mice for the distal appendage protein CEP164 reveal its essential roles in airway multiciliated cell differentiation.

Multiciliated cells of the airways, brain ventricles, and female reproductive tract provide the motive force for mucociliary clearance, cerebrospinal fluid circulation, and ovum transport. Despite their clear importance to human biology and health, the molecular mechanisms underlying multiciliated cell differentiation are poorly understood. Prior studies implicate the distal appendage/transition fiber protein CEP164 as a central regulator of primary ciliogenesis; however, its role in multiciliogenesis remains unknown.

Myelination is delayed during postnatal brain development in the mdx mouse model of Duchenne muscular dystrophy.

Background: In Duchenne muscular dystrophy (DMD), the loss of the dystrophin component of the dystrophin-glycoprotein complex (DGC) compromises plasma membrane integrity in skeletal muscle, resulting in extensive muscle degeneration. In addition, many DMD patients exhibit brain deficits in which the cellular etiology remains poorly understood. We recently found that dystroglycan, a receptor component of the DGC that binds intracellularly to dystrophin, regulates the development of oligodendrocytes, the myelinating glial cells of the brain.

Behavioral experiences as drivers of oligodendrocyte lineage dynamics and myelin plasticity.

Many behavioral experiences are known to promote hippocampal neurogenesis. In contrast, the ability of behavioral experiences to influence the production of oligodendrocytes and myelin sheath formation remains relatively unknown. However, several recent studies indicate that voluntary exercise and environmental enrichment can positively influence both oligodendrogenesis and myelination, and that, in contrast, social isolation can negatively influence myelination.

Dystroglycan Suppresses Notch to Regulate Stem Cell Niche Structure and Function in the Developing Postnatal Subventricular Zone.

While the extracellular matrix (ECM) is known to regulate neural stem cell quiescence in the adult subventricular zone (SVZ), the function of ECM in the developing SVZ remains unknown. Here, we report that the ECM receptor dystroglycan regulates a unique developmental restructuring of ECM in the early postnatal SVZ. Dystroglycan is furthermore required for ependymal cell differentiation and assembly of niche pinwheel structures, at least in part by suppressing Notch activation in radial glial cells, which leads to the increased expression of MCI, Myb, and FoxJ1, transcriptional regulators necessary for acquisition of the multiciliated phenotype.

Laminin promotes metalloproteinase-mediated dystroglycan processing to regulate oligodendrocyte progenitor cell proliferation.

The cell surface receptor dystroglycan mediates interactions between oligodendroglia and laminin-211, an extracellular matrix protein that regulates timely oligodendroglial development. However, dystroglycan's precise role in oligodendroglial development and the potential mechanisms to regulate laminin-dystroglycan interactions remain unknown. Here we report that oligodendroglial dystroglycan is cleaved by metalloproteinases, thereby uncoupling oligodendroglia from laminin binding.

The extracellular matrix protein laminin α2 regulates the maturation and function of the blood-brain barrier.

Laminins are major constituents of the gliovascular basal lamina of the blood-brain barrier (BBB); however, the role of laminins in BBB development remains unclear. Here we report that Lama2(-/-) mice, lacking expression of the laminin α2 subunit of the laminin-211 heterotrimer expressed by astrocytes and pericytes, have a defective BBB in which systemically circulated tracer leaks into the brain parenchyma. The Lama2(-/-) vascular endothelium had significant abnormalities, including altered integrity and composition of the endothelial basal lamina, inappropriate expression of embryonic vascular endothelial protein MECA32, substantially reduced pericyte coverage, and tight junction abnormalities.

Laminin regulates postnatal oligodendrocyte production by promoting oligodendrocyte progenitor survival in the subventricular zone.

The laminin family of extracellular matrix proteins are expressed broadly during embryonic brain development, but are enriched at ventricular and pial surfaces where laminins mediate radial glial attachment during corticogenesis. In the adult brain, however, laminin distribution is restricted, yet is found within the vascular basal lamina and associated fractones of the ventricular zone (VZ)-subventricular zone (SVZ) stem cell niche, where laminins regulate adult neural progenitor cell proliferation. It remains unknown, however, if laminins regulate the wave of oligodendrogenesis that occurs in the neonatal/early postnatal VZ-SVZ.

Dystroglycan promotes filopodial formation and process branching in differentiating oligodendroglia.

During central nervous system (CNS) development, individual oligodendrocytes myelinate multiple axons, thus requiring the outgrowth and extensive branching of oligodendroglial processes. Laminin (Lm)-deficient mice have a lower percentage of myelinated axons, which may indicate a defect in the ability to properly extend and branch processes. It remains unclear, however, to what extent extracellular matrix (ECM) receptors contribute to oligodendroglial process remodeling itself.

Derivation of enriched oligodendrocyte cultures and oligodendrocyte/neuron myelinating co-cultures from post-natal murine tissues.

Identifying the molecular mechanisms underlying OL development is not only critical to furthering our knowledge of OL biology, but also has implications for understanding the pathogenesis of demyelinating diseases such as Multiple Sclerosis (MS). Cellular development is commonly studied with primary cell culture models. Primary cell culture facilitates the evaluation of a given cell type by providing a controlled environment, free of the extraneous variables that are present in vivo.

Glia unglued: how signals from the extracellular matrix regulate the development of myelinating glia.

The health and function of the nervous system relies on glial cells that ensheath neuronal axons with a specialized plasma membrane termed myelin. The molecular mechanisms by which glial cells target and enwrap axons with myelin are only beginning to be elucidated, yet several studies have implicated extracellular matrix proteins and their receptors as being important extrinsic regulators. This review provides an overview of the extracellular matrix proteins and their receptors that regulate multiple steps in the cellular development of Schwann cells and oligodendrocytes, the myelinating glia of the PNS and CNS, respectively, as well as in the construction and maintenance of the myelin sheath itself.

Dystroglycan modulates the ability of insulin-like growth factor-1 to promote oligodendrocyte differentiation.

The adhesion receptor dystroglycan positively regulates terminal differentiation of oligodendrocytes, but the mechanism by which this occurs remains unclear. Using primary oligodendrocyte cultures, we identified and examined a connection between dystroglycan and the ability of insulin-like growth factor-1 (IGF-1) to promote oligodendrocyte differentiation. Consistent with previous reports, treatment with exogenous IGF-1 caused an increase in MBP protein that was preceded by activation of PI3K (AKT) and MAPK (ERK) signaling pathways.

Tyrosine phosphatases Shp1 and Shp2 have unique and opposing roles in oligodendrocyte development.

Oligodendrocyte progenitor cells first proliferate to generate sufficient cell numbers and then differentiate into myelin-producing oligodendrocytes. The signal transduction mediators that underlie these events, however, remain poorly understood. The tyrosine phosphatase Shp1 has been linked to oligodendrocyte differentiation as Shp1-deficient mice show hypomyelination.

Laminin alters fyn regulatory mechanisms and promotes oligodendrocyte development.

Mutations in LAMA2, the gene for the extracellular matrix protein laminin-alpha2, cause a severe muscular dystrophy termed congenital muscular dystrophy type-1A (MDC1A). MDC1A patients have accompanying CNS neural dysplasias and white matter abnormalities for which the underlying mechanisms remain unknown. Here, we report that in laminin-deficient mice, oligodendrocyte development was delayed such that oligodendrocyte progenitors accumulated inappropriately in adult brains.

beta1 integrin maintains integrity of the embryonic neocortical stem cell niche.

During embryogenesis, the neural stem cells (NSC) of the developing cerebral cortex are located in the ventricular zone (VZ) lining the cerebral ventricles. They exhibit apical and basal processes that contact the ventricular surface and the pial basement membrane, respectively. This unique architecture is important for VZ physical integrity and fate determination of NSC daughter cells.

Beta1 integrins are required for normal CNS myelination and promote AKT-dependent myelin outgrowth.

Oligodendrocytes in the central nervous system (CNS) produce myelin sheaths that insulate axons to ensure fast propagation of action potentials. beta1 integrins regulate the myelination of peripheral nerves, but their function during the myelination of axonal tracts in the CNS is unclear. Here we show that genetically modified mice lacking beta1 integrins in the CNS present a deficit in myelination but no defects in the development of the oligodendroglial lineage.

Identification of dystroglycan as a second laminin receptor in oligodendrocytes, with a role in myelination.

Developmental abnormalities of myelination are observed in the brains of laminin-deficient humans and mice. The mechanisms by which these defects occur remain unknown. It has been proposed that, given their central role in mediating extracellular matrix (ECM) interactions, integrin receptors are likely to be involved.