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

Abstract

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.

Semaphorin 3C as a Therapeutic Target in Prostate and Other Cancers

“…Outside of cancer, whilst primarily noted for their participation in the development of the nervous system [10,41,42,43,44,45,46,47,48,49], research has also established the importance of SEMA3C and its receptors in cardiovascular [11,50,51,52,53,54,55,56], retinal [57] and renal [58] development, as well as chondrogenesis [59], and alveolar growth and repair [60]. In addition, SEMA3C has been associated with other human conditions including autism [61], Takao syndrome [62], Alzheimer’s [63] and Hirschsprung disease [64].…”

Construction and reconstruction of brain circuits: normal and pathological axon guidance

“…a) (Niquille et al ). Once CC axons have reached and crossed the midline, this attractive signal is switched off (Mire et al ). This coincides with an up‐regulation of the transmembrane protein ephrin‐B1 in post‐crossing CC axons.…”

“…This coincides with an up‐regulation of the transmembrane protein ephrin‐B1 in post‐crossing CC axons. Interestingly, ephrin‐B1 possesses a unique Asparagine residue (N‐139), not shared by other ephrins, which once glycosylated can allow ephrin‐B1 interaction with Nrp1 and silence Sema3C/Nrp1 attraction (Mire et al ) (Fig. b).…”

Sensory Axon Growth Requires Spatiotemporal Integration of CaSR and TrkB Signaling

“…The signals involved for fine-tuning neuronal growth are diversified (e.g., through several ligands binding to one receptor) (Chao, 2003;Zhou et al, 2008;Dudanova and Klein, 2013) or ligands binding directly to their receptors or through a coreceptor (Chauvet et al, 2007;Bellon et al, 2010;Song et al, 2015;Mire et al, 2018), eventually leading to differential changes of the cytoskeleton (Bashaw and Klein, 2010).…”

“…Additionally, spatial and temporal expression of receptors and coreceptors modulates responses depending on developmental states (Dickson and Gilestro, 2006;Mire et al, 2012Mire et al, , 2018. Furthermore, several studies have reported that signaling cascades interact to generate complex cellular behaviors (Bourne and Nicoll, 1993;Cornell and Kimelman, 1994;Prehoda and Lim, 2002;McClean et al, 2007).…”