Dorsal spinal cord inhibits oligodendrocyte development

Oligodendrocytes are the myelinating cells of the mammalian central nervous system. In the mouse spinal cord, oligodendrocytes are generated from strictly restricted regions of the ventral ventricular zone. To investigate how they originate from these specific regions, we used an explant culture system of the E12 mouse cervical spinal cord and hindbrain. In this culture system O4(+) cells were first detected along the ventral midline of the explant and were subsequently expanded to the dorsal region similar to in vivo. When we cultured the ventral and dorsal spinal cords separately, a robust increase in the number of O4(+) cells was observed in the ventral fragment. The number of both progenitor cells and mature cells also increased in the ventral fragment. This phenomenon suggests the presence of inhibitory factor for oligodendrocyte development from dorsal spinal cord. BMP4, a strong candidate for this factor that is secreted from the dorsal spinal cord, did not affect oligodendrocyte development. Previous studies demonstrated that signals from the notochord and ventral spinal cord, such as sonic hedgehog and neuregulin, promote the ventral region-specific development of oligodendrocytes. Our present study demonstrates that the dorsal spinal cord negatively regulates oligodendrocyte development.     

Purinergic signaling in oligodendrocyte development and function

Myelin, an insulating membrane that enables rapid action potential propagation, is an essential component of an efficient, functional vertebrate nervous system. Oligodendrocytes, the myelinating glia of the central nervous system (CNS), produce myelin throughout the CNS, which requires continuous proliferation, migration, and differentiation of oligodendrocyte progenitor cells. Because myelination is essential for efficient neurotransmission, researchers hypothesize that neuronal signals may regulate the cascade of events necessary for this process. The ability of oligodendrocytes and oligodendrocyte progenitor cells to detect and respond to neuronal activity is becoming increasingly appreciated, although the specific signals involved are still a matter of debate. Recent evidence from multiple studies points to purinergic signaling as a potential regulator of oligodendrocyte development and differentiation. Adenosine triphosphate (ATP) and its derivatives are potent signaling ligands with receptors expressed on many populations of cells in the nervous system, including cells of the oligodendrocyte lineage. Release of ATP into the extracellular space can initiate a multitude of signaling events, and these downstream signals are specific to the particular purinergic receptor (or receptors) expressed, and whether enzymes are present to hydrolyze ATP to its derivatives adenosine diphosphate and adenosine, each of which can activate their own unique downstream signaling cascades. This review will introduce purinergic signaling in the CNS and discuss evidence for its effects on oligodendrocyte proliferation, differentiation, and myelination. We will review sources of extracellular purines in the nervous system and how changes in purinergic receptor expression may be coupled to oligodendrocyte differentiation. We will also briefly discuss purinergic signaling in injury and diseases of the CNS.

     

FGF modulates the PDGF-driven pathway of oligodendrocyte development

PDGF promotes the growth of oligodendrocyte type-2 astrocyte (O-2A) glial progenitor cells and allows their timely differentiation into oligodendrocytes, the CNS myelin-forming cells. We demonstrate that basic FGF is a potent mitogen for brain O-2A progenitor cells, but blocks their differentiation into oligodendrocytes. Treatment with basic FGF also influences the level of expression of PDGF receptors on O-2A progenitor cells. These cells express only the alpha chain PDGF receptor, and the levels of PDGF alpha receptors decrease as the cells differentiate. In contrast, basic FGF maintains a high level of functionally responsive PDGF alpha receptors in O-2A progenitors. Thus basic FGF activates a signaling pathway that can positively regulate PDGF receptors in O-2A progenitor cells. In this way basic FGF or an FGF-like factor may modulate the production of myelin-forming cells in the CNS.     

A cell-intrinsic timer that operates during oligodendrocyte development

Multicellular organisms develop on a predictable schedule that depends on both cell-intrinsic timers and sequential cell-cell interactions mediated by extracellular signals. The interplay between intracellular timers and extracellular signals is well illustrated by the development of oligodendrocytes, the cells that make the myelin in the vertebrate central nervous system. An intrinsic timing mechanism operates in each oligodendrocyte precursor cell to limit the length of time the cell divides before terminally differentiating. This mechanism consists of two components, a timing component, which depends on the mitogen platelet-derived growth factor (PDGF) and measures elapsed time, and an effector component, which depends on thyroid hormone and stops cell division and initiates differentiation at the appropriate time. The cell-cycle inhibitor p27/Kip1 accumulates in the precursor cells as they proliferate and is part of both components of the timer. It seems likely that similar timing mechanisms operate in other cell lineages. BioEssays 22:64-71, 2000.     

MicroRNA: Key regulators of oligodendrocyte development and pathobiology

MicroRNAs (miRNAs or miRs) are a group of small non-coding RNAs that function through binding to messenger RNA (mRNA) targets and downregulating gene expression. miRNAs have been shown to regulate many cellular functions including proliferation, differentiation, development and apoptosis. Recently, evidence has grown which shows the involvement of miRs in oligodendrocyte (OL) specification and development. In particular, miRs-138, -219, -338, and -9 have been classified as key regulators of OL development, acting at various points in the OL lineage and influencing precursor cell transit into mature myelinating OLs. Many studies have emerged which link miRNAs with OL and myelin pathology in various central nervous system (CNS) diseases including multiple sclerosis (MS), ischemic stroke, spinal cord injury, and adult-onset autosomal dominant leukodystrophy (ADLD).     

Intrinsic and extrinsic inhibition of oligodendrocyte development by rat retina

Cell patterning in the vertebrate CNS reflects the combination of localized cell induction, migration and differentiation. A striking example of patterning is the myelination of visual system. In many species, retinal ganglion cell axons are myelinated in the optic nerve but are unmyelinated in the retina. Here, we confirm that rat and mouse retina lack oligodendrocytes and their precursors and identify multiple mechanisms that might contribute to their absence. Soluble cues from embryonic retina inhibit the induction of oligodendrocytes from neural stem cells and their differentiation from optic nerve precursors. This inhibition is mediated by retinal-derived BMPs. During development BMPs are expressed in the retina and addition of the BMP antagonist Noggin reversed retinal inhibition of oligodendrocyte development. The lack of retinal oligodendrocytes does not simply reflect expression of BMPs, since no oligodendrocytes or their precursors developed when embryonic retinal cells were grown in the presence of Noggin and/or inductive cues such as Shh and IGF-1. Similarly, injection of Noggin into the postnatal rat eye failed to induce oligodendrocyte differentiation. These data combined with the proposed inhibition of OPC migration by molecules selectively expressed at the nerve retina junction suggest that multiple mechanisms combine to suppress retinal myelination during development.     

Getting a GR(i)P on oligodendrocyte development

One of the most extensively studied of mammalian cells is the oligodendrocyte, the myelin-forming cell of the central nervous system. The ancestry and development of this cell have been studied with every approach utilized by developmental biologists. Such detailed efforts have the potential of providing paradigms of relevance to those interested in analyzing the ancestry and development of any cell type.One of the striking features of studies on the development of oligodendrocytes is that different analytical approaches have led to strikingly different theoretical views regarding the ancestry of these cells. On one extreme is the hypothesis that the steps leading to the generation of oligodendrocytes begin with the generation of a glial-restricted precursor (GRP) cell from neuroepithelial stem cells. GRP cells are thought to be capable of giving rise to all glial cells (including oligodendrocytes and multiple astrocyte populations), but not to neurons, a process that appears to require progression through further stages of greater lineage restriction. On the other extreme is the hypothesis that oligodendrocytes are derived from a precursor cell that generates only motor neurons and oligodendrocytes, with astrocytes being generated through a separate lineage. In this review, we critically consider the various contributions to understanding the ancestry of oligodendrocytes, with particular attention to the respective merits of the GRP cell vs. the motor neuron-oligodendrocyte precursor (MNOP) cell hypothesis. We draw the conclusion that, at present, the strengths of the GRP cell hypothesis outweigh those of the MNOP hypothesis and other hypotheses suggesting oligodendrocytes are developmentally more related to motor neurons than to astrocytes. Moreover, it is clear from existing data that, following the period of motor neuron generation, the major glial precursor cell in the embryonic spinal cord is the GRP cell, and that multiple previous studies on the earliest stages of oligodendrocyte generation in the developing spinal cord have been focused on a differentiation stage of GRP cells.     

Roles for p53 and p73 during oligodendrocyte development

Oligodendrocytes make myelin in the vertebrate central nervous system (CNS). They develop from oligodendrocyte precursor cells (OPCs), most of which divide a limited number of times before they stop and differentiate. OPCs can be purified from the developing rat optic nerve and stimulated to proliferate in serum-free culture by PDGF. They can be induced to differentiate in vitro by either thyroid hormone (TH) or PDGF withdrawal. It was shown previously that a dominant-negative form of p53 could inhibit OPC differentiation induced by TH but not by PDGF withdrawal, suggesting that the p53 family of proteins might play a part in TH-induced differentiation. As the dominant-negative p53 used inhibited all three known p53 family members - p53, p63 and p73 - it was uncertain which family members are important for this process. Here, we provide evidence that both p53 and p73, but not p63, are involved in TH-induced OPC differentiation and that p73 also plays a crucial part in PDGF-withdrawal-induced differentiation. This is the first evidence for a role of p73 in the differentiation of a normal mammalian cell.     

A role for Noggin in the development of oligodendrocyte precursor cells

Oligodendrocyte precursor cells (OPCs) can be differentiated in culture into either oligodendrocytes or type-2 astrocytes (2As), depending on the culture conditions. Whereas oligodendrocyte development can occur in the absence of inducing signals, 2A development apparently cannot. Fetal calf serum (FCS) and bone morphogenetic proteins (BMPs) are powerful inducers of 2A development in culture, but there is no compelling evidence that OPCs develop into astrocytes in vivo. We show here that BMPs are made by glial cells in the developing rat optic nerve, raising the question of why 2As do not normally develop in the optic nerve. We demonstrate that the BMP antagonist Noggin is strongly expressed by both OPCs and type-1 astrocytes in the developing optic nerve. We also show that depletion of Noggin by a small interference RNA inhibits OPC proliferation and induces 2A differentiation in the presence of a low, non-2A-inducing concentration of FCS. By contrast, enforced expression of Noggin in OPCs blocks FCS-induced 2A differentiation. These findings suggest that BMPs in FCS are largely responsible for the 2A-inducing activity of FCS and that Noggin may normally inhibit the formation of 2As in the developing CNS.     

Exposure to serotonin adversely affects oligodendrocyte development and myelination in vitro

Serotonin (5‐hydroxytryptamine, 5‐HT) has been implicated to play critical roles in early neural development. Recent reports have suggested that perinatal exposure to selective serotonin reuptake inhibitors (SSRIs) resulted in cortical network miswiring, abnormal social behavior, callosal myelin malformation, as well as oligodendrocyte (OL) pathology in rats. To gain further insight into the cellular and molecular mechanisms underlying SSRIs‐induced OL and myelin abnormalities, we investigated the effect of 5‐HT exposure on OL development, cell death, and myelination in cell culture models. First, we showed that 5‐HT receptor 1A and 2A subtypes were expressed in OL lineages, using immunocytochemistry, Western blot, as well as intracellular Ca²⁺ measurement. We then assessed the effect of serotonin exposure on the lineage development, expression of myelin proteins, cell death, and myelination, in purified OL and neuron‐OL myelination cultures. For pure OL cultures, our results showed that 5‐HT exposure led to disturbance of OL development, as indicated by aberrant process outgrowth and reduced myelin proteins expression. At higher doses, such exposure triggered a development‐dependent cell death, as immature OLs exhibited increasing susceptibility to 5‐HT treatment compared to OL progenitor cells (OPC). We showed further that 5‐HT‐induced immature OL death was mediated at least partially via 5‐HT2A receptor, since cell death could be mimicked by 5‐HT2A receptor agonist 1‐(2,5‐dimethoxy‐4‐iodophenyl)‐2‐aminopropane hydrochloride, (±)‐2,5‐dimethoxy‐4‐iodoamphetamine hydrochloride, but atten‐uated by pre‐treatment with 5‐HT2A receptor antagonist ritanserin. Utilizing a neuron‐OL myelination co‐culture model, our data showed that 5‐HT exposure significantly reduced the number of myelinated internodes. In contrast to cell injury observed in pure OL cultures, 5‐HT exposure did not lead to OL death or reduced OL density in neuron‐OL co‐cultures. However, abnormal patterns of contactin‐associated protein (Caspr) clustering were observed at the sites of Node of Ranvier, suggesting that 5‐HT exposure may affect other axon‐derived factors for myelination. In summary, this is the first study to demonstrate that manipulation of serotonin levels affects OL development and myelination, which may contribute to altered neural connectivity noted in SSRIs‐treated animals.

     

Integrins direct Src family kinases to regulate distinct phases of oligodendrocyte development

Specific integrins expressed on oligodendrocytes, the myelin-forming cells of the central nervous system, promote either differentiation and survival or proliferation by amplification of growth factor signaling. Here, we report that the Src family kinases (SFKs) Fyn and Lyn regulate each of these distinct integrin-driven behaviors. Fyn associates with alpha6beta1 and is required to amplify platelet-derived growth factor survival signaling, to promote myelin membrane formation, and to switch neuregulin signaling from a phosphatidylinositol 3-kinase to a mitogen-activated protein kinase pathway (thereby changing the response from proliferation to differentiation). However, earlier in the lineage Lyn, not Fyn, is required to drive alphaVbeta3-dependent progenitor proliferation. The two SFKs respond to integrin ligation by different mechanisms: Lyn, by increased autophosphorylation of a catalytic tyrosine; and Fyn, by reduced Csk phosphorylation of the inhibitory COOH-terminal tyrosine. These findings illustrate how different SFKs can act as effectors for specific cell responses during development within a single cell lineage, and, furthermore, provide a molecular mechanism to explain similar region-specific hypomyelination in laminin- and Fyn-deficient mice.     

Wnt signaling controls the timing of oligodendrocyte development in the spinal cord

During spinal cord development, oligodendrocytes are generated from a restricted region of the ventral ventricular zone and then spread out into the entire spinal cord. These events are controlled by graded inductive and repressive signals derived from a local organizing center. Sonic hedgehog was identified as an essential ventral factor for oligodendrocyte lineage specification, whereas the dorsal cue was less clear. In this study, Wnt proteins were identified as the dorsal factors that directly inhibit oligodendrocyte development. Wnt signaling through a canonical beta-catenin pathway prevents its differentiation from progenitor to an immature state. Addition of rmFz-8/Fc, a Wnt antagonist, increased the number of immature oligodendrocytes in the spinal cord explant culture, demonstrating that endogenous Wnt signaling controls oligodendrocyte development.     

Regulation of Wolffian duct development

Wolffian ducts (WDs) are the embryonic structures that form the male internal genitalia. These ducts develop in both the male and female embryo. However, in the female they subsequently regress, whereas in the male they are stabilised by testosterone. The WDs then develop into separate but contiguous organs, the epididymis, vas deferens and seminal vesicles. Recently, considerable progress has been made in identifying genes that are involved in these different stages of development which is described in this review. In addition, WD development in (atypical forms of) cystic fibrosis and intersex disorders, such as the complete androgen insensitivity syndrome, 17beta-hydroxysteroid dehydrogenase deficiency and LH-receptor defects, is discussed. The apparent increase in male reproductive tract disorders is briefly discussed from the perspective of the potential endocrine-disrupting effects of the numerous chemicals in the environment to which the developing male foetus can be exposed.