In vivo experiments in zebrafish determine that CNS-derived glial cells contribute to the myelinating population of cells in the PNS and ensure that CNS and PNS glia remain segregated.
In the mature vertebrate nervous system, central and peripheral nervous system (CNS and PNS, respectively) GLIA myelinate distinct motor axon domains at the motor exit point transition zone (MEP TZ). How these cells preferentially associate with and myelinate discrete, non-overlapping CNS versus PNS axonal segments, is unknown. Using in vivo imaging and genetic cell ablation in zebrafish, we demonstrate that radial glia restrict migration of PNS glia into the spinal cord during development. Prior to development of radial glial endfeet, peripheral cells freely migrate back and forth across the MEP TZ. However, upon maturation, peripherally located cells never enter the CNS. When we ablate radial glia, peripheral glia ectopically migrate into the spinal cord during developmental stages when they would normally be restricted. These findings demonstrate that radial glia contribute to both CNS and PNS development and control the unidirectional movement of glial cell types across the MEP TZ early in development.
SUMMARY During development, oligodendrocyte progenitor cells (OPCs) migrate extensively throughout the spinal cord. However, their migration is restricted at transition zones (TZs). At these specialized locations, unique glial cells in both zebrafish and mice play a role in preventing peripheral OPC migration, but the mechanisms of this regulation are not understood. To elucidate the mechanisms that mediate OPC segregation at motor exit point (MEP) TZs, we performed an unbiased small-molecule screen. Using chemical screening and in vivo imaging, we discovered that inhibition of A2a adenosine receptors (ARs) causes ectopic OPC migration out of the spinal cord. We provide in vivo evidence that neuromodulation, partially mediated by adenosine, influences OPC migration specifically at the MEP TZ. This work opens exciting possibilities for understanding how OPCs reach their final destinations during development and identifies mechanisms that could promote their migration in disease.
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. Keywords: ATP, glia, myelin, oligodendrocyte, purine, purinergic receptors. Oligodendrocytes perform the crucial function of synthesizing myelin sheaths to insulate CNS axons and ensure rapid action potential propagation. Myelin production and remodeling continues through adulthood, and the synthesis of new myelin sheaths even plays a role in learning, and differentiation of new oligodendrocytes (OL) from oligodendrocyte progenitor cells (OPC) is an essential part of this process (Gibson et al. 2014 Abbreviations used: 2MeSATP, 2-methylthioadenosine triphosphate is a potent P2Y purinoceptor agonist; A1, A2a, A2b, A3 Receptors, adenosine receptors; ADP, adenosine diphosphate; ALS, amyotrophic lateral sclerosis; AMP, adenosine monophosphate; ATP, adenosine triphosphate; BzATP, 2'(3')-O-(4-benzoylbenzoyl)adenosine-5'-triphosphate tri(triethylammonium) salt, P2X7 agonist and P2X1/P2Y1 partial agonist; cAMP, cyclic adenosine monophosphate; CGS21680, adenosine A2 receptor agonist; CNS, central nervous system; CPA, N6-cyclopentyladenosine, a A1 selective agonist; EAE, experimental autoimmune encephalomyelitis; Enpp2, ectonucleot...
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