Myelin basic protein mRNA levels affect myelin sheath dimensions, architecture, plasticity, and density of resident glial cells.

Myelin Basic Protein (MBP) is essential for both elaboration and maintenance of CNS myelin, and its reduced accumulation results in hypomyelination. How different Mbp mRNA levels affect myelin dimensions across the lifespan and how resident glial cells may respond to such changes are unknown. Here, to investigate these questions, we used enhancer-edited mouse lines that accumulate Mbp mRNA levels ranging from 8% to 160% of wild type.

Selective PDE4 subtype inhibition provides new opportunities to intervene in neuroinflammatory versus myelin damaging hallmarks of multiple sclerosis.

Multiple sclerosis (MS) is a chronic autoimmune disease of the central nervous system (CNS) characterized by focal inflammatory lesions and prominent demyelination. Even though the currently available therapies are effective in treating the initial stages of disease, they are unable to halt or reverse disease progression into the chronic progressive stage. Thus far, no repair-inducing treatments are available for progressive MS patients.

Piezo channels contribute to the regulation of myelination in Schwann cells.

Peripheral nerves and Schwann cells have to sustain constant mechanical constraints, caused by developmental growth as well as stretches associated with movements of the limbs and mechanical compressions from daily activities. In Schwann cells, signaling molecules sensitive to stiffness or stretch of the extracellular matrix, such as YAP/TAZ, have been shown to be critical for Schwann cell development and peripheral nerve regeneration. YAP/TAZ have also been suggested to contribute to tumorigenesis, neuropathic pain, and inherited disorders.

Oriented and sustained protein expression on biomimicking electrospun fibers for evaluating functionality of cells.

A proper protein orientation is often required in order to achieve specific protein-receptor interaction to elicit a desired biological response. Here, we present a Protein A-based biomimicking platform that is capable of efficiently orienting proteins for evaluating cellular behaviour. By absorbing Protein A onto aligned bio-mimicking polycaprolactone (PCL) fibers, we demonstrate that protein binding could be retained on these fibers for at least 7 days under physiologically relevant conditions.

Biomimicking Fiber Platform with Tunable Stiffness to Study Mechanotransduction Reveals Stiffness Enhances Oligodendrocyte Differentiation but Impedes Myelination through YAP-Dependent Regulation.

A key hallmark of many diseases, especially those in the central nervous system (CNS), is the change in tissue stiffness due to inflammation and scarring. However, how such changes in microenvironment affect the regenerative process remains poorly understood. Here, a biomimicking fiber platform that provides independent variation of fiber structural and intrinsic stiffness is reported.

A Neuron-Free Microfiber Assay to Assess Myelin Sheath Formation.

Important advances in our understanding of oligodendrocyte precursor cell biology and differentiation have stemmed from in vitro experiments using cultures of isolated primary oligodendrocyte precursor cells. To examine the process of myelination in the final stages of oligodendrocyte development, experimental systems have previously been limited to models utilizing neurons. Recent advances in three-dimensional culture systems, however, have opened the possibility to observe myelin sheath formation with only one cell type, the oligodendrocyte precursor cell.

Scaffold-Mediated Sustained, Non-viral Delivery of miR-219/miR-338 Promotes CNS Remyelination.

The loss of oligodendrocytes (OLs) and subsequently myelin sheaths following injuries or pathologies in the CNS leads to debilitating functional deficits. Unfortunately, effective methods of remyelination remain limited. Here, we present a scaffolding system that enables sustained non-viral delivery of microRNAs (miRs) to direct OL differentiation, maturation, and myelination.

Microfiber drug/gene delivery platform for study of myelination.

Unlabelled: Our ability to rescue functional deficits after demyelinating diseases or spinal cord injuries is limited by our lack of understanding of the complex remyelination process, which is crucial to functional recovery. In this study, we developed an electrospun suspended poly(ε-caprolactone) microfiber platform to enable the screening of therapeutics for remyelination. As a proof of concept, this platform employed scaffold-mediated non-viral delivery of a microRNA (miR) cocktail to promote oligodendrocyte precursor cells (OPCs) differentiation and myelination.

Activin receptors regulate the oligodendrocyte lineage in health and disease.

The most prevalent neurological disorders of myelin include perinatal brain injury leading to cerebral palsy in infants and multiple sclerosis in adults. Although these disorders have distinct etiologies, they share a common neuropathological feature of failed progenitor differentiation into myelin-producing oligodendrocytes and lack of myelin, for which there is an unmet clinical need. Here, we reveal that a molecular pathology common to both disorders is dysregulation of activin receptors and that activin receptor signaling is required for the majority of myelin generation in development and following injury.

Intrinsic and adaptive myelination-A sequential mechanism for smart wiring in the brain.

The concept of adaptive myelination-myelin plasticity regulated by activity-is an important advance for the field. What signals set up the adaptable pattern in the first place? Here we review work that demonstrates an intrinsic pathway within oligodendrocytes requiring only an axon-shaped substrate to generate multilayered and compacted myelin sheaths of a physiological length. Based on this, we discuss a model we proposed in 2015 which argues that myelination has two phases-intrinsic and then adaptive-which together generate "smart wiring," in which active axons become more myelinated.

Reconstitution of Phospholipase A2-Dependent Golgi Membrane Tubules.

The Golgi complex is the Grand Central Station of intracellular membrane trafficking in the secretory and endocytic pathways. Anterograde and retrograde export of cargo from the Golgi complex involves a complex interplay between the formation of coated vesicles and membrane tubules, although much less is known about tubule-mediated trafficking. Recent advances using in vitro assays have identified several cytoplasmic phospholipase A2 (PLA2) enzymes that are required for the biogenesis of membrane tubules and their roles in the functional organization of the Golgi complex.

CNS Myelin Sheath Lengths Are an Intrinsic Property of Oligodendrocytes.

Since Río-Hortega's description of oligodendrocyte morphologies nearly a century ago, many studies have observed myelin sheath-length diversity between CNS regions. Myelin sheath length directly impacts axonal conduction velocity by influencing the spacing between nodes of Ranvier. Such differences likely affect neural signal coordination and synchronization.

Gβ1γ2 activates phospholipase A-dependent Golgi membrane tubule formation.

Heterotrimeric G proteins transduce the ligand binding of transmembrane G protein coupled receptors into a variety of intracellular signaling pathways. Recently, heterotrimeric Gβγ subunit signaling at the Golgi complex has been shown to regulate the formation of vesicular transport carriers that deliver cargo from the Golgi to the plasma membrane. In addition to vesicles, membrane tubules have also been shown to mediate export from the Golgi complex, which requires the activity of cytoplasmic phospholipase A (PLA) enzyme activity.

PAFAH Ib phospholipase A2 subunits have distinct roles in maintaining Golgi structure and function.

Recent studies showed that the phospholipase subunits of Platelet Activating Factor Acetylhydrolase (PAFAH) Ib, α1 and α2 partially localize to the Golgi complex and regulate its structure and function. Using siRNA knockdown of individual subunits, we find that α1 and α2 perform overlapping and unique roles in regulating Golgi morphology, assembly, and secretory cargo trafficking. Knockdown of either α1 or α2 reduced secretion of soluble proteins, but neither single knockdown reduced secretion to the same degree as knockdown of both.

A PLA1-2 punch regulates the Golgi complex.

The mammalian Golgi complex, trans Golgi network (TGN) and ER-Golgi intermediate compartment (ERGIC) are comprised of membrane cisternae, coated vesicles and membrane tubules, all of which contribute to membrane trafficking and maintenance of their unique architectures. Recently, a new cast of players was discovered to regulate the Golgi and ERGIC: four unrelated cytoplasmic phospholipase A (PLA) enzymes, cPLA(2)α (GIVA cPLA(2)), PAFAH Ib (GVIII PLA(2)), iPLA(2)-β (GVIA-2 iPLA(2)) and iPLA(1)γ. These ubiquitously expressed enzymes regulate membrane trafficking from specific Golgi subcompartments, although there is evidence for some functional redundancy between PAFAH Ib and cPLA(2)α.

The phospholipase A₂ enzyme complex PAFAH Ib mediates endosomal membrane tubule formation and trafficking.

Previous studies have shown that membrane tubule-mediated export from endosomal compartments requires a cytoplasmic phospholipase A(2) (PLA(2)) activity. Here we report that the cytoplasmic PLA(2) enzyme complex platelet-activating factor acetylhydrolase (PAFAH) Ib, which consists of α1, α2, and LIS1 subunits, regulates the distribution and function of endosomes. The catalytic subunits α1 and α2 are located on early-sorting endosomes and the central endocytic recycling compartment (ERC) and their overexpression, but not overexpression of their catalytically inactive counterparts, induced endosome membrane tubules.

The phospholipase complex PAFAH Ib regulates the functional organization of the Golgi complex.

We report that platelet-activating factor acetylhydrolase (PAFAH) Ib, comprised of two phospholipase A(2) (PLA(2)) subunits, alpha1 and alpha2, and a third subunit, the dynein regulator lissencephaly 1 (LIS1), mediates the structure and function of the Golgi complex. Both alpha1 and alpha2 partially localize on Golgi membranes, and purified catalytically active, but not inactive alpha1 and alpha2 induce Golgi membrane tubule formation in a reconstitution system. Overexpression of wild-type or mutant alpha1 or alpha2 revealed that both PLA(2) activity and LIS1 are important for maintaining Golgi structure.