Mutually Repulsive EphA7–EfnA5 Organize Region-to-Region Corticopontine Projection by Inhibiting Collateral Extension

Abstract

Coordination of skilled movements and motor planning relies on the formation of regionally restricted brain circuits that connect cortex with subcortical areas during embryonic development. Layer 5 neurons that are distributed across most cortical areas innervate the pontine nuclei (basilar pons) by protrusion and extension of collateral branches interstitially along their corticospinal extending axons. Pons-derived chemotropic cues are known to attract extending axons, but molecules that regulate collateral extension to create regionally segregated targeting patterns have not been identified. Here, we discovered that EphA7 and EfnA5 are expressed in the cortex and the basilar pons in a region-specific and mutually exclusive manner, and that their repulsive activities are essential for segregating collateral extensions from corticospinal axonal tracts in mice. Specifically, EphA7 and EfnA5 forward and reverse inhibitory signals direct collateral extension such that EphA7-positive frontal and occipital cortical areas extend their axon collaterals into the EfnA5-negative rostral part of the basilar pons, whereas EfnA5-positive parietal cortical areas extend their collaterals into the EphA7negative caudal part of the basilar pons. Together, our results provide a molecular basis that explains how the corticopontine projection connects multimodal cortical outputs to their subcortical targets.

A transcriptomic taxonomy of mouse brain-wide spinal projecting neurons

“…5d,g ). These guidance molecules have been suggested to regulate topographic mapping of the corticospinal tract 46 , and their continued expression in adult SPNs may suggest a potential role in maintaining their respective spinal terminations. Finally, by analysing the higher sequencing depth SSv4 data, we identified a set of differentially expressed genes between cervical- and lumbar-/dual-projecting neurons in CSNs and RuSNs (Fig.…”

Src/Fas2-dependent Ephrin phosphorylation initiates Eph/Ephrin reverse signaling through Rac1 to shape columnar units in the fly brain

“…Ephrin and Eph have been shown to be involved in not only diverse developmental processes but also a variety of diseases (9)(10)(11)(12). They can both act as ligand and receptor for forward and reverse signaling through cell-to-cell communication (13)(14)(15)(16).…”

A model for generating differences in microtubules between axonal branches depending on the distance from terminals

“…The extension and elimination of specific branches establish neuronal subtype specific axonal branch patterns (O' Leary and Koester, 1993). It is considered that this process is regulated by axon guidance molecules expressed in a region-dependent manner (Iguchi et al, 2021). In the case of motor neuron axons innervating the muscles, multiple axons contact the same synaptic site on muscles by forming highly branched terminal arbors at the neonatal stage.…”