Paranode stability requires UNC5B expression by oligodendrocytes

Abstract

Netrins are secreted proteins that direct cell migration and axon extension in the developing CNS and are essential for normal neural development. In the mature CNS, netrin-1 is expressed by neurons and oligodendrocytes and implicated in the stability of axo-oligodendroglial paranodal junctions. Here we report that the netrin receptor UNC5B is highly expressed by mature oligodendrocytes and enriched at paranodes. We demonstrate that paranodes become disorganized following conditional deletion of UNC5B in oligodendrocytes, with disruption of the interface between glial loops and detachment of glial loops from the axon. Examining axoglial domain segregation, Caspr1 and Kv1.1 disperse along the axon, internodes shorten, and the periodicity of compact myelin is reduced, indicating significant breakdown of myelin organization in UNC5B cKOs. Paranodal disruption and axoglial domain disorganization progressively worsen with age and a delay in motor learning develops specifically in aged animals that lack oligodendroglial UNC5B. We detect reduced amounts of oligodendroglial Claudin-11 and JAM-C proteins in UNC5B knockouts, suggesting that disruption of the specialized autotypic junctions between glial loops may underlie paranodal disorganization. Our findings reveal an essential contribution of oligodendroglial UNC5B at axoglial junctions that is required for the stability of mature myelin.

Mitochondrial dynamics and bioenergetics regulated by netrin‐1 in oligodendrocytes

“…Netrin-1 and its receptors are required for the maintenance of paranodal junctions in the mature CNS (Bull et al, 2014;de Faria et al, 2020;Jarjour et al, 2008). Here, we showed that focal netrin-1 signaling is sufficient to remodel the local distribution of myelin proteins PLP and CNP near the bead surface, and recruit paranodal proteins DCC (Bull et al, 2014;Jarjour et al, 2008), NF155 (Bhat et al, 2001;Boyle et al, 2001;Charles et al, 2002;Pillai et al, 2009;Sherman et al, 2005) and ZO-1 (Ogawa & Rasband, 2009;Poliak et al, 2002).…”

“…Netrin-1 is expressed by myelinating oligodendrocytes and locally enriched at central nervous system (CNS) paranodes (Bull et al, 2014;Jarjour et al, 2008;Manitt et al, 2001;Manitt, Thompson, & Kennedy, 2004). Selective deletion of the netrin-1 receptors deleted in colorectal carcinoma (DCC) or UNCoordinated-5 homologue B from oligodendrocytes severely disrupts paranodal junctions (Bull et al, 2014;de Faria et al, 2020). Emerging evidence indicates that netrins influence the formation of epithelial cell-cell junctions (Beamish, Hinck, & Kennedy, 2018), and direct the local recruitment of synaptic proteins and formation of synaptic specializations in neurons (Colon-Ramos, Margeta, & Shen, 2007;Goldman et al, 2013;Lai Wing Sun, Correia, & Kennedy, 2011;Poon, Klassen, & Shen, 2008).…”