In the developing central nervous system (CNS), oligodendrocyte precursor cells (OPCs) migrate along blood vessels and are widely distributed in the CNS. Meanwhile, OPCs require survival factors from the extracellular microenvironment. In other tissues, laminins, heterotrimetric (αβγ) extracellular matrix proteins, promote cell migration and survival. However, the expression pattern and functions of laminins in OPC development remain poorly understood. In the present study, we first investigated the expression of laminin α chains, which bind to cell surface receptors such as integrins, in the postnatal murine brain. We found that laminin α1, α2, α4, and α5 chains were expressed around blood vessels and OPCs attached the laminin α chain-positive vessels. We then evaluated the effect of these laminins on OPCs activity using recombinant laminin E8s (LME8s) that are minimally active fragments of the laminin isoforms. OPCs attached on LM211E8, LM411E8, and LM511E8, containing laminin α2, α4, and α5 chains, respectively, through integrin β1. Further, these three LME8s promoted migration of OPCs, and OPC survival was prolonged on either LM411E8 or LM511E8 via the activation of focal adhesion kinase. Together, our findings suggest that laminins expressed surrounding blood vessels positively regulate migration and survival of OPCs through the integrin β1-FAK pathway.

Oligodendrocytes are myelin-forming cells in the central nervous system (CNS). The development of oligodendrocytes is regulated by a large number of molecules, including extracellular matrix (ECM) proteins that are relatively less characterized. Here, we review the molecular functions of the major ECM proteins in oligodendrocyte development and pathology. Among the ECM proteins, laminins are positive regulators in oligodendrocyte survival, differentiation, and/or myelination in the CNS. Conversely, fibronectin, tenascin-C, hyaluronan, and chondroitin sulfate proteoglycans suppress the differentiation and myelination. Tenascin-R shows either positive or negative functions in these activities. In addition, the extracellular domain of the transmembrane protein teneurin-4, which possesses the sequence homology with tenascins, promotes the differentiation of oligodendrocytes. The activities of these ECM proteins are exerted through binding to the cellular receptors and co-receptors, such as integrins and growth factor receptors, which induces the signaling to form the elaborated and functional structure of myelin. Further, the ECM proteins dynamically change their structures and functions at the pathological conditions as multiple sclerosis. The ECM proteins are a critical player to serve as a component of the microenvironment for oligodendrocytes in their development and pathology.

In the spinal cord, the axonal tracts with various caliber sizes are myelinated by oligodendrocytes and function as high-velocity ways for motor and sensory nerve signals. In some neurological disorders, such as multiple sclerosis, demyelination of small caliber axons is observed in the spinal cord. While type I/II oligodendrocytes among the four types are known to myelinate small diameter axons, their characteristics including identification of regulating molecules have not been understood yet. Here, we first found that in the wild-type mouse spinal cord, type I/II oligodendrocytes, positive for carbonic anhydrase II (CAII), were located in the corticospinal tract, fasciculus gracilis, and the inside part of ventral funiculus, in which small diameter axons existed. The type I/II oligodendrocytes started to appear between postnatal day (P) 7 and 11. We further analyzed the type I/II oligodendrocytes in the mutant mice, whose small diameter axons were hypomyelinated due to the deficiency of teneurin-4. In the teneurin-4 deficient mice, type I/II oligodendrocytes were significantly reduced, and the onset of the defect was at P11. Our results suggest that CAII-positive type I/II oligodendrocytes myelinate small caliber axons in the spinal cord and teneurin-4 is the responsible molecule for the generation of type I/II oligodendrocytes.

In the central nervous system, oligodendrocytes (OLs) form myelin sheaths that accomplish the efficient transmission of nerve conduction for optimal motor and cognitive functions. OL development and differentiation are regulated by a variety of molecules, including extracellular matrix (ECM) proteins. ECM proteins are also useful as substrates for OL culture. However, the functions of ECM proteins in OL development and myelination remain unclear, and only a limited number of ECM proteins have been characterized and used in in vitro experiments. Here, we investigated the expression and function of laminin (LM) isoforms in OL differentiation and myelination. We found that LM α1, α2, and α4 chains were expressed around blood vessels at the stage of myelination in mice. Functional analyses using recombinant proteins of LM isoforms containing α1, α2, and α4 chains revealed that LM411 and LM411E8, the integrin binding domain of LM411, possessed significant activities in myelin membrane formation of OLs. Furthermore, the peptide A4G47 derived from LM411E8 promoted the activity, which provides evidence of the first peptide in OL myelin formation from ECM proteins. Our findings facilitate a better understanding of ECM functions in OL biology and the development of a new material in OL myelination.