The Neuromodulator Adenosine Regulates Oligodendrocyte Migration at Motor Exit Point Transition Zones

Abstract

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.

Spinal cord precursors utilize neural crest cell mechanisms to generate hybrid peripheral myelinating glia

“…In contrast, we did not observe any MEP glia in the PNS of foxd3 −/− larvae (Figure 3A,C). However, we did observe ectopic, peripheral OPCs along motor nerves in foxd3 −/− larvae (Figure 3A,D), which is consistent with the loss of peripheral MEP glia (Fontenas et al, 2019; Smith et al, 2014).…”

“…To investigate whether axonally-derived nrg1 is sufficient to induce MEP glial migration, we genetically overexpressed human Neuregulin 1 type III (hNrg1) in all neurons, including spinal cord neurons (Perlin et al, 2011), using neuroD:gal4;UAS:hNrg1 embryos, where neuroD regulatory sequences drive expression of the transcription factor Gal4 (Fontenas et al, 2019) and UAS enhancer sequences drive expression of human Neuregulin 1 type III (Perlin et al, 2011). In these embryos, we detected krox20 + Schwann cells in the white matter of the spinal cord (Figure 8 - figure supplement 1A) as previously described (Perlin et al, 2011).…”

“…During nervous system development, neural progenitors orchestrate the formation of the brain, spinal cord, and peripheral nerves by generating neurons and glia. Although components of the CNS and PNS are traditionally thought to segregate, growing numbers of studies show the selective and bidirectional permeability of nervous system TZs (Clark et al, 2014; Fontenas et al, 2019; Garcia-Diaz et al, 2019; Green, Nebiolo, & Smith, 2019; Kucenas, Takada, et al, 2008; Smith et al, 2016; Smith et al, 2014; Zhu et al, 2019). Development of myelinating cells such as oligodendrocytes and Schwann cells has extensively been studied, but development of MEP glia, a novel population of CNS-derived, peripheral glia that freely migrate across TZs, remains poorly understood.…”

“…Until recently, TZs were thought to be selectively permeable to only axons, and the establishment of the territories occupied by glial cells remained poorly described and not well understood. Recent work now demonstrates that MEP TZs are occupied by dynamic glial cells and are precisely regulated over the course of nervous system development (Fanny Coulpier et al, 2010; Fontenas et al, 2019; Kucenas, Takada, et al, 2008; Kucenas, Wang, Knapik, & Appel, 2009; Smith, Johnson, Welsh, Barresi, & Kucenas, 2016; Smith, Morris, Welsh, & Kucenas, 2014; Zhu et al, 2019). CNS components such as oligodendrocyte (OL) lineage cells, motor neurons, and radial glia segregate and function in the spinal cord, and Schwann cells segregate and function in the PNS.…”

“…Once in the periphery, MEP glia tightly associate with spinal motor root axons and ultimately myelinate the most proximal axonal segments along the nerve, and therefore, participate in the fast conduction of action potentials from the CNS to the muscle (Fontenas & Kucenas, 2018; Smith et al, 2014). Previously, we showed that MEP glia also function to restrict highly migratory OPCs to the spinal cord (Fontenas et al, 2019; Smith et al, 2014). While we are beginning to appreciate the functional roles of MEP glia (Fontenas et al, 2019; Smith et al, 2014), we still lack a complete understanding of their development.…”