Oligodendrocyte precursors guide interneuron migration by unidirectional contact repulsion

Abstract

In the forebrain, ventrally derived oligodendrocyte precursor cells (vOPCs) travel tangentially toward the cortex together with cortical interneurons. Here, we tested in the mouse whether these populations interact during embryogenesis while migrating. By coupling histological analysis of genetic models with live imaging, we show that although they are both attracted by the chemokine Cxcl12, vOPCs and cortical interneurons occupy mutually exclusive forebrain territories enriched in this chemokine. Moreover, first-wave vOPC depletion selectively disrupts the migration and distribution of cortical interneurons. At the cellular level, we found that by promoting unidirectional contact repulsion, first-wave vOPCs steered the migration of cortical interneurons away from the blood vessels to which they were both attracted, thereby allowing interneurons to reach their proper cortical territories.

Competitive migration steers interneurons

During brain development, both interneurons and oligodendrocyte precursor cells travel tangentially from their birthplace to the location where they will function. Lepiemme et al . looked for interactions during the migratory phase of mouse brain development. Although born in the same regions and destined to be intertwined in the cortex, nterneurons and oligodendrocyte precursor cells differed in how they got there. Oligodendrocyte precursor cells tended to track along blood vessels, whereas interneurons migrated in collectively organized streams. Imaging showed that oligodendrocyte precursor cells drove migrating interneurons away from the blood vessels. Left to fend for themselves, the interneurons organized in migratory streams. —PJH

Abstract

During mouse development, migrating cortical interneurons get steered away from blood vessels.

Abstract

INTRODUCTION

The cerebral cortex is an evolutionarily advanced brain region made of cellular layers tangentially organized into areas that serve higher cognitive functions. During development, most cortical interneurons (hereafter called interneurons) are born in the ventral forebrain, where some progenitors concomitantly generate oligodendrocyte precursor cells (OPCs). OPCs differentiate into oligodendrocytes, the principal functions of which are to wrap axons with myelin to support the rapid saltatory conduction of action potentials and to provide metabolic support to neurons in the postnatal brain. Three distinct populations of OPCs have been identified in the forebrain. These cells are born as successive waves with a defined spatiotemporal pattern, and they all migrate from their birthplace to colonize the brain. The two initial waves are born in the ventral forebrain and named vOPCs. They migrate together with the interneurons toward the cortex, whereas the third OPC wave is generated locally around birth by some progenitors of the cortical wall. Despite their distinct origin, all OPC lineages converge at the transcriptional level, which may reflect their contribution to myelination.

RATIONALE

While migrating, some neural cells promote transient cellular interactions that confer upon them roles additional to those played once integrated into the cortical network. Accordingly, recent studies have reported that some first-wave vOPCs establish synaptic contacts with lineage-related interneurons during early postnatal periods. It is intriguing that a large fraction of the first-wave vOPCs do not contribute to synaptogenesis and are eliminated during the second postnatal week. Here, we assessed whether vOPCs play additional noncanonical functions during brain development by testing whether they cross-talk with interneurons to support their concomitant migration to the cerebral cortex.

RESULTS

We hypothesized that some early functions of vOPCs would rely on their spatiotemporal origin, further defining their field of possible interactions with neighboring cells. Despite being born in shared germinal regions of the ventral forebrain, vOPCs and interneurons occupy mutually exclusive territories while migrating. Live imaging of both cell populations in brain slices from mouse embryos showed that first-wave vOPCs and interneurons use distinct migration strategies to reach the cortex. Cortical interneurons navigate into organized streams within the parenchyma, whereas first-wave vOPCs prefer migration along blood vessels. The ordered migration of interneurons in cortical streams relies mostly on gradients of chemoattractant molecules such as Cxcl12, to which interneurons are responsive through their expression of the Cxcr4 receptor. This chemokine is also abundantly released by endothelial cells covering the complex and dense network of growing blood vessels that perfuse the ganglionic eminences and later the cortical wall. A long-standing question in the field of brain development is how cortical interneurons cope with different sources, and thus gradients of Cxcl12, to properly navigate within the cortex. Here, we show that first-wave vOPCs, which are also attracted by Cxcl12, migrate along blood vessels and promote unidirectional contact repulsion to repel migrating interneurons from blood vessels. This cellular mechanism, which is not shared by second-wave vOPCs, relies on the expression of the semaphorin 6a/6b by first-wave vOPCs that binds and activates the plexin A3 receptors expressed at the surface of interneurons. This atypical signaling triggers interneuron polarity reversal, preventing them from clustering around blood vessels and allowing them to follow the cortical Cxcl12 gradient (released by intermediate progenitors and meningeal cells) to reach and settle in their cortical layer in a timely manner. Moreover, a prolonged interaction of migrating interneurons with cells that release high levels of Cxcl12, such as endothelial cells, may not only bias their migration directionality but also reduce their motility through a sustained activation of Cxr4 receptors by Cxcl12, leading to their internalization.

CONCLUSION

During brain development, vOPCs and interneurons are born in the ventral forebrain and migrate concomitantly along tangential routes to reach the cerebral cortex. Here, we show by coupling histological analysis of mouse genetic models with live imaging that, while being responsive to Cxcl12 gradients, both cell populations occupy mutually exclusive forebrain territories enriched in this chemokine. Live-imaging analyses demonstrated that first-wave, but not second-wave, vOPCs perform unidirectional contact repulsion on interneurons. This mechanism steers interneurons away from blood vessels that release Cxcl12, thereby allowing them to follow cortical gradients of this chemokine to later settle in their cortical layer. This mode of contact repulsion is specific to first-wave vOPC-interneuron pairs and distinct from self-repulsion. It relies on the activation of an atypical semaphorin-plexin signaling that induces directional change of interneurons upon their polarity reversal. Whether the specificity of this interaction relies on the degree of interneuron maturation and/or the signaling toolbox of vOPCs belonging in two distinct waves remains to be determined.