Developmental Upregulation of Ephrin-B1 Silences Sema3C/Neuropilin-1 Signaling during Post-crossing Navigation of Corpus Callosum Axons

• Published in: Current biology Vol. 28; no. 11; pp. 1768 - 1782.e4
• Main Authors: Mire, Erik, Hocine, Mélanie, Bazellières, Elsa, Jungas, Thomas, Davy, Alice, Chauvet, Sophie, Mann, Fanny
• Format: Journal Article
• Language: English
• Published: England Elsevier Ltd 04.06.2018; Elsevier
• Subjects: axon guidance; corpus callosum; cortex; ephrins; Life Sciences; neuropilins; semaphorins; cortex; neuropilins; ephrins; semaphorins; corpus callosum; axon guidance
• ISSN: 0960-9822; 1879-0445
• DOI: 10.1016/j.cub.2018.04.026

The corpus callosum is the largest commissure in the brain, whose main function is to ensure communication between homotopic regions of the cerebral cortex. During fetal development, corpus callosum axons (CCAs) grow toward and across the brain midline and then away on the contralateral hemisphere to their targets. A particular feature of this circuit, which raises a key developmental question, is that the outgoing trajectory of post-crossing CCAs is mirror-symmetric with the incoming trajectory of pre-crossing axons. Here, we show that post-crossing CCAs switch off their response to axon guidance cues, among which the secreted Semaphorin-3C (Sema3C), that act as attractants for pre-crossing axons on their way to the midline. This change is concomitant with an upregulation of the surface protein Ephrin-B1, which acts in CCAs to inhibit Sema3C signaling via interaction with the Neuropilin-1 (Nrp1) receptor. This silencing activity is independent of Eph receptors and involves a N-glycosylation site (N-139) in the extracellular domain of Ephrin-B1. Together, our results reveal a molecular mechanism, involving interaction between the two unrelated guidance receptors Ephrin-B1 and Nrp1, that is used to control the navigation of post-crossing axons in the corpus callosum. [Display omitted] •Callosal axons change their response to guidance cues after midline crossing•Post-crossing callosal axons switch off responsiveness to attractive Sema3C•Ephrin-B1 is developmentally upregulated on post-crossing callosal axons•Ephrin-B1 interacts with Nrp1 to silence Sema3C independently of Eph receptors Mire et al. discover a unique interaction between Ephrin-B1 and Nrp1 that turns off the axonal response to the Sema3C attractant. This molecular on/off switch allows callosal axons to move across mirror-symmetrical gradients of Sema3C on both sides of the brain midline.