RESUMO
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.
Assuntos
Adenosina/farmacologia , Movimento Celular/efeitos dos fármacos , Placa Motora/embriologia , Neurotransmissores/farmacologia , Oligodendroglia/efeitos dos fármacos , Medula Espinal/embriologia , Animais , Animais Geneticamente Modificados , Padronização Corporal/fisiologia , Diferenciação Celular/efeitos dos fármacos , Embrião não Mamífero , Feminino , Masculino , Placa Motora/citologia , Neurônios Motores/efeitos dos fármacos , Neurônios Motores/fisiologia , Oligodendroglia/fisiologia , Medula Espinal/citologia , Medula Espinal/efeitos dos fármacos , Células-Tronco/efeitos dos fármacos , Células-Tronco/fisiologia , Peixe-Zebra/embriologiaRESUMO
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.
Assuntos
Oligodendroglia/citologia , Oligodendroglia/fisiologia , Receptores Purinérgicos/metabolismo , Transdução de Sinais/fisiologia , Animais , Diferenciação Celular/fisiologia , Sistema Nervoso Central/citologia , Sistema Nervoso Central/fisiologia , Humanos , Células-Tronco Neurais/citologia , Células-Tronco Neurais/fisiologia , Neurogênese/fisiologiaRESUMO
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. GLIA 2016. GLIA 2016;64:1138-1153.
Assuntos
Movimento Celular/fisiologia , Sistema Nervoso/citologia , Neuroglia/fisiologia , Medula Espinal/citologia , Animais , Animais Geneticamente Modificados , Embrião não Mamífero , Proteínas Luminescentes/genética , Proteínas Luminescentes/metabolismo , Neurônios Motores/fisiologia , Neurônios Motores/ultraestrutura , Proteínas do Tecido Nervoso/genética , Proteínas do Tecido Nervoso/metabolismo , Sistema Nervoso/embriologia , Neuroglia/ultraestrutura , Medula Espinal/embriologia , Peixe-Zebra , Proteínas de Peixe-Zebra/genética , Proteínas de Peixe-Zebra/metabolismoRESUMO
Rapid conduction of action potentials along motor axons requires that oligodendrocytes and Schwann cells myelinate distinct central and peripheral nervous system (CNS and PNS) domains along the same axon. Despite the importance of this arrangement for nervous system function, the mechanisms that establish and maintain this precise glial segregation at the motor exit point (MEP) transition zone are unknown. Using in vivo time-lapse imaging in zebrafish, we observed that prior to myelination, oligodendrocyte progenitor cells (OPCs) extend processes into the periphery via the MEP and immediately upon contact with spinal motor root glia retract back into the spinal cord. Characterization of the peripheral cell responsible for repelling OPC processes revealed that it was a novel, CNS-derived population of glia we propose calling MEP glia. Ablation of MEP glia resulted in the absence of myelinating glia along spinal motor root axons and an immediate breach of the MEP by OPCs. Taken together, our results identify a novel population of CNS-derived peripheral glia located at the MEP that selectively restrict the migration of OPCs into the periphery via contact-mediated inhibition.