The cell biology of CNS myelination

Abstract

Myelination of axons in the central nervous system results from the remarkable ability of oligodendrocytes to wrap multiple axons with highly specialized membrane. Because myelin membrane grows as it ensheaths axons, cytoskeletal rearrangements that enable ensheathment must be coordinated with myelin production. Because the myelin sheaths of a single oligodendrocyte can differ in thickness and length, mechanisms that coordinate axon ensheathment with myelin growth likely operate within individual oligodendrocyte processes. Recent studies have revealed new information about how assembly and disassembly of actin filaments helps drive the leading edge of nascent myelin membrane around and along axons. Concurrently, other investigations have begun to uncover evidence of communication between axons and oligodendrocytes that can regulate myelin formation.

Figure 1. Recent findings underlying oligodendrocyte precursor cell (OPCs) migration, motility, and distribution

a) Embryonic migration along blood vessels is mediated by OPC-endothelial interactions via Wnt -Cxcr4 signaling [6]. b) The modulation of Rho GTPases by chondroitin proteoglycan, NG2, regulates OPC polarity and directional migration [8]. c) Local proliferation (yellow arrowheads) regulates OPC density in response to OPC turnover (differentiating OPC, purple) [11]; recent work indicates netrin-1 signaling may underlie this spatial homeostasis [13].

Figure 2. Features of oligodendrocytes amenable to neuronal activity-induced plasticity. 1)

Generation of new oligodendrocytes: optogenetic stimulation or motor learning increases differentiation of oligodendrocyte precursor cells (OPCs) [15,48]. 2) Myelin sheath thickness: life experience or optogenetic stimulation increases myelin thickness relative to axonal diameter (g ratio) [44,48]. 3) Myelin sheath length: axon conduction times are regulated by differential axon diameter and myelin sheath length [50, (Ford,Grothe 15), 81]. 4) Myelin sheath number: electrical activity of axons or life experience modulates the number of myelin sheaths [47,49]. 5) Selection of axons to myelinate: activity-evoked vesicle release increases the stability and growth of nascent myelin sheaths [54].

Figure 3. Potential roles of axon secreted factors in driving myelin sheath formation

In response to electrical activity, axon vesicles release growth factors, such as NrgI and BDNF, and glutamate. Receptor tyrosine kinase signaling, activated by growth factors, sensitizes NMDA receptors to glutamate and possibly initiates signal transduction that promotes myelin gene transcription and local myelin protein translation, possibly via PI3K/Akt/mTOR signaling (dashed arrows). NMDA receptor signaling leads to Fyn kinase activity, promoting MBP translation from transcripts that are transported into oligodendrocyte processes on microtubules. MBP production near the point of axon contact initiates disassembly of actin filaments, enabling axon wrapping via membrane spreading.