Summary MicroRNAs (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 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.
An essential feature of vertebrate neural development is ensheathment of axons with myelin, an insulating membrane formed by oligodendrocytes. Not all axons are myelinated, but mechanisms directing myelination of specific axons are unknown. Using zebrafish we show that activity-dependent secretion stabilizes myelin sheath formation on select axons. When VAMP2-dependent exocytosis is silenced in single axons, oligodendrocytes preferentially ensheath neighboring axons. Nascent sheaths formed on silenced axons are shorter in length, but when activity of neighboring axons is also suppressed, inhibition of sheath growth is relieved. Using in vivo time-lapse microscopy, we show that only 25% of oligodendrocyte processes that initiate axon wrapping are stabilized during normal development, and that initiation does not require activity. Instead, oligodendrocyte processes wrapping silenced axons are retracted more frequently. We propose that axon selection for myelination results from excessive and indiscriminate initiation of wrapping followed by refinement that is biased by activity-dependent secretion from axons.
Myelinating oligodendrocytes arise from migratory and proliferative oligodendrocyte progenitor cells (OPCs). Complete myelination requires that oligodendrocytes be uniformly distributed and form numerous, periodically spaced membrane sheaths along the entire length of target axons. Mechanisms that determine spacing of oligodendrocytes and their myelinating processes are not known. Using in vivo time-lapse confocal microscopy, we show that zebrafish OPCs continuously extend and retract numerous filopodium-like processes as they migrate and settle into their final positions. Process remodeling and migration paths are highly variable and seem to be influenced by contact with neighboring OPCs. After laser ablation of oligodendrocyte-lineage cells, nearby OPCs divide more frequently, orient processes toward the ablated cells and migrate to fill the unoccupied space. Thus, process activity before axon wrapping might serve as a surveillance mechanism by which OPCs determine the presence or absence of nearby oligodendrocyte-lineage cells, facilitating uniform spacing of oligodendrocytes and complete myelination.
Motor function requires that motor axons extend from the spinal cord at regular intervals and that they are myelinated by Schwann cells. Little attention has been given to another cellular structure, the perineurium, which ensheaths the motor nerve, forming a flexible, protective barrier. Consequently, the origin of perineurial cells and their roles in motor nerve formation are poorly understood. Using time-lapse imaging in zebrafish, we show that perineurial cells are born in the CNS, arising as ventral spinal-cord glia before migrating into the periphery. In embryos lacking perineurial glia, motor neurons inappropriately migrated outside of the spinal cord and had aberrant axonal projections, indicating that perineurial glia carry out barrier and guidance functions at motor axon exit points. Additionally, reciprocal signaling between perineurial glia and Schwann cells was necessary for motor nerve ensheathment by both cell types. These insights reveal a new class of CNSborn glia that critically contributes to motor nerve development.The formation of spinal motor nerves requires coordinated interactions between several types of cells. Motor neurons extend axons into developing muscle fields from the spinal cord through segmentally positioned motor exit points (MEPs). These axons encounter neural crest-derived boundary cap cells clustered at MEPs, which permit the axons, but not the cell bodies, to exit from the spinal cord 1 . As motor axons approach their targets, they are sequentially wrapped and then myelinated by Schwann cells, glial cells that also develop from neural crest.The myelinated motor nerve is surrounded by a flexible cellular sheath called the perineurium, first described in 1841 by Henle and later named by Key and Retzius 2 . The perineurium consists of uninterrupted, concentric rings of flattened cells that are connected by tight junctions and encase motor nerves from the MEP to the neuromuscular junction (NMJ) 2-7 . The perineurial sheath serves as a barrier, protecting axons from ionic flux, toxins and infection 4, 8-10 . Therefore, formation of the perineurium is essential for peripheral nerve function.Correspondence should be addressed to B.A. (b.appel@vanderbilt.edu). AUTHOR CONTRIBUTIONS S.K. produced all of the data except for the electron microscopy images shown in Figure 5c NIH-PA Author ManuscriptNIH-PA Author Manuscript NIH-PA Author ManuscriptPrevious studies have suggested that, during development, the perineurium appears to form by a series of steps in which nearby mesenchymal cells first assemble as a loosely organized tube around the nerve and then mature to create a multilayered barrier 11 . The maturation step requires the signaling molecule Desert hedgehog (Dhh), which is expressed by Schwann cells. In the absence of Dhh, the perineurium is disorganized and is permeable to macromolecules and inflammatory cells 12 . Although these studies revealed a critical feature of perineurial cell differentiation, the origin of perineurial cells and how they initially associate ...
Oligodendrocytes are produced from the same region of the ventral spinal cord that earlier generated motor neurons in bird and rodent embryos. Motor neuron and oligodendrocyte precursor cells express Olig genes, which encode basic helix-loop-helix transcription factors that play important roles in the development of both motor neurons and oligodendrocytes. We found that oligodendrocytes develop similarly in zebrafish embryos, in that they arise from ventral spinal cord and migrate to new positions. Developing primary motor neurons and oligodendrocytes express olig2 as do neural plate cells that give rise to both primary motor neurons and oligodendrocytes. Loss of olig2 function prevented primary motor neuron and oligodendrocyte development, whereas olig2 overexpression promoted formation of excess primary motor neurons and oligodendrocytes. We provide genetic evidence that Hedgehog signaling is required for zebrafish olig2 expression and oligodendrocyte development. However, olig2 overexpression did not promote primary motor neuron or oligodendrocyte development in embryos with reduced Hedgehog signaling activity. One possibility consistent with these data is that Hedgehog signaling, partly by inducing olig2 expression, specifies neural precursor cells that have potential for primary motor neuron or oligodendrocyte fate.
scite is a Brooklyn-based organization that helps researchers better discover and understand research articles through Smart Citations–citations that display the context of the citation and describe whether the article provides supporting or contrasting evidence. scite is used by students and researchers from around the world and is funded in part by the National Science Foundation and the National Institute on Drug Abuse of the National Institutes of Health.
hi@scite.ai
10624 S. Eastern Ave., Ste. A-614
Henderson, NV 89052, USA
Copyright © 2024 scite LLC. All rights reserved.
Made with 💙 for researchers
Part of the Research Solutions Family.