Fine-Tuning Oligodendrocyte Development by microRNAs

Myelination of axons by oligodendrocytes in the central nervous system is essential for normal neuronal functions. The failure of remyelination due to injury or pathological insults results in devastating demyelinating diseases. Oligodendrocytes originate in restricted regions of the embryonic ventral neural tube. After migration to populate all areas of the brain and spinal cord, oligodendrocyte precursors undergo a temporally well-defined series of molecular and structural changes, ultimately culminating in the cessation of proliferation, and the elaboration of a highly complex myelin sheath. The emergence of microRNAs (miRNAs) as potent regulators of gene expression at the posttranscriptional level has broad implications in all facets of cell biology. Recent studies have demonstrated a critical role of miRNAs in oligodendrocyte development, including cell proliferation, differentiation, and myelin formation. In this review, we will highlight and discuss the recent understanding of functional links of miRNAs to regulatory networks for central myelination, as well as perspectives on the role of miRNAs in demyelinating diseases

Oligodendrocyte Progenitor Programming and Reprogramming: Toward Myelin Regeneration

Demyelinating diseases such as multiple sclerosis (MS) are among the most disabling and cost-intensive neurological disorders. The loss of myelin in the central nervous system, produced by oligodendrocytes (OLs), impairs saltatory nerve conduction, leading to motor and cognitive deficits. Immunosuppression therapy has a limited efficacy in MS patients, arguing for a paradigm shift to strategies that target OL lineage cells to achieve myelin repair. The inhibitory microenvironment in MS lesions abrogates the expansion and differentiation of resident OL precursor cells (OPCs) into mature myelin-forming OLs. Recent studies indicate that OPCs display a highly plastic ability to differentiate into alternative cell lineages under certain circumstances. Thus, understanding the mechanisms that maintain and control OPC fate and differentiation into mature OLs in a hostile, non-permissive lesion environment may open new opportunities for regenerative therapies. In this review, we will focus on 1) the plasticity of OPCs in terms of their developmental origins, distribution, and differentiation potentials in the normal and injured brain; 2) recent discoveries of extrinsic and intrinsic factors and small molecule compounds that control OPC specification and differentiation; and 3) therapeutic potential for motivation of neural progenitor cells and reprogramming of differentiated cells into OPCs and their likely impacts on remyelination. OL-based therapies through activating regenerative potentials of OPCs or cell replacement offer exciting opportunities for innovative strategies to promote remyelination and neuroprotection in devastating demyelinating diseases like MS

Decision to Use an Airframe Parachute in a Flight Training Environment

The purpose of this study was to complete a qualitative analysis of the decision-making process used by pilots to determine whether or not to deploy an airframe parachute system. A sample of participants from the subject university’s flight training program was selected to complete a scripted simulator flight in instrument flight conditions. During the flight, participants experienced an engine failure while enroute during IFR conditions. The script was examined and validated by an expert panel who determined use of the airframe parachute was the most appropriate outcome for the scenario. Interestingly, only 9 of the 21 participants responded as expected by the expert panel and deployed the parachute system; only three of the nine followed the correct deployment procedure as outlined in the Pilot’s Operating Handbook. Analysis of a post-flight survey completed by participants provides insights into the decision-making process used by pilots and offers explanations on why or why not participants used the airframe parachute

An ‘oligarchy’ rules neural development.

Review Oligodendrocytes engage in complex interactions with nerve cell bodies and axons in the CNS, notably in the formation of myelin sheaths Transcription factors as arbiters of oligodendroglial cell fate The roles of transcription factors in neuronal cell fate specification in the CNS have been intensively studied over the past decade (reviewed in Ref

Exact calculation of the skyrmion lifetime in a ferromagnetic Bose condensate

The tunneling rate of a skyrmion in ferromagnetic spin-1/2 Bose condensates through an off-centered potential barrier is calculated exactly with the periodic instanton method. The prefactor is shown to depend on the chemical potential of the core atoms, at which level the atom tunnels. Our results can be readily extended to estimate the lifetime of other topological excitations in the condensate, such as vortices and monopoles.Comment: 16 pages, 4 figures, to appear Phys. Rev.

Impurity states in antiferromagnetic Iron Arsenides

We explore theoretically impurity states in the antiferromagnetic spin-density wave state of the iron arsenide. Two types of impurity models are employed: one has only the intraband scattering while the other has both the intraband and interband scattering with the equal strength. Interestingly, the impurity bound state is revealed around the impurity site in the energy gap for both models. However, the impurity state is doubly degenerate with respect to spin for the first case; while the single impurity state is observed in either the spin-up or spin-down channel for the second one. The impurity-induced variations of the local density of states are also examined.Comment: 4 pages, 2 figure

MicroRNA-Mediated Control of Oligodendrocyte Differentiation

SummaryMicroRNAs (miRNAs) regulate various biological processes, but evidence for miRNAs that control the differentiation program of specific neural cell types has been elusive. To determine the role of miRNAs in the formation of myelinating oligodendrocytes, we selectively deleted a miRNA-processing enzyme, Dicer1, in oligodendrocyte lineage cells. Mice lacking Dicer1 display severe myelinating deficits despite an expansion of the oligodendrocyte progenitor pool. To search for miRNAs responsible for the induction of oligodendrocyte maturation, we identified miR-219 and miR-338 as oligodendrocyte-specific miRNAs in spinal cord. Overexpression of these miRNAs is sufficient to promote oligodendrocyte differentiation. Additionally, blockage of these miRNA activities in oligodendrocyte precursor culture and knockdown of miR-219 in zebrafish inhibit oligodendrocyte maturation. miR-219 and miR-338 function in part by directly repressing negative regulators of oligodendrocyte differentiation, including transcription factors Sox6 and Hes5. These findings illustrate that miRNAs are important regulators of oligodendrocyte differentiation, providing new targets for myelin repair

Dual regulatory switch through interactions of Tcf7l2/Tcf4 with stage-specific partners propels oligodendroglial maturation

Constitutive activation of Wnt/β-catenin inhibits oligodendrocyte myelination. Tcf7l2/Tcf4, a β-catenin transcriptional partner, is required for oligodendrocyte differentiation. How Tcf7l2 modifies β-catenin signalling and controls myelination remains elusive. Here we define a stage-specific Tcf7l2-regulated transcriptional circuitry in initiating and sustaining oligodendrocyte differentiation. Multistage genome occupancy analyses reveal that Tcf7l2 serially cooperates with distinct co-regulators to control oligodendrocyte lineage progression. At the differentiation onset, Tcf7l2 interacts with a transcriptional co-repressor Kaiso/Zbtb33 to block β-catenin signalling. During oligodendrocyte maturation, Tcf7l2 recruits and cooperates with Sox10 to promote myelination. In that context, Tcf7l2 directly activates cholesterol biosynthesis genes and cholesterol supplementation partially rescues oligodendrocyte differentiation defects in Tcf712 mutants. Together, we identify stage-specific co-regulators Kaiso and Sox10 that sequentially interact with Tcf7l2 to coordinate the switch at the transitions of differentiation initiation and maturation during oligodendrocyte development, and point to a previously unrecognized role of Tcf7l2 in control of cholesterol biosynthesis for CNS myelinogenesis