EphrinB3/EphA4-Mediated Guidance of Ascending and Descending Spinal Tracts

The spinal cord contains many descending and ascending longitudinal tracts whose development appears to be controlled by distinct guidance systems. We identified a population of dorsal spinal neurons marked by coexpression of the transcription factor Zic2 and the guidance receptor EphA4. Zic2+;EphA4+ neurons are surrounded by mechanosensory terminals, suggesting innervation by mechanoreceptor afferents. Their axons form an ipsilateral ascending pathway that develops during embryogenesis and projects within the ventral aspect of the dorsal funiculus, the same location as the descending corticospinal tract (CST), which develops postnatally. Interestingly, the same guidance mechanism, namely, ephrinB3-induced EphA4 forward signaling, is required for the guidance of both ascending and descending axon tracts. Our analysis of conditional EphA4 mutant mice also revealed that the development of the dorsal funiculus occurs independently of EphA4 expression in descending CST axons and is linked to the distribution of Zic2+;EphA4+ spinal neurons and the formation of the ascending pathway. •Zic2+;EphA4+ spinal neurons receive mechanosensory input•Zic2+;EphA4+ cells form an ipsilateral ascending projection•Location of Zic2+;EphA4+ cells controls dorsal funiculus development•EphrinB3 and EphA4 guide ascending and descending spinal tracts Paixão et al. identified dorsal spinal neurons that are innervated by mechanoreceptor afferents and form an ipsilateral ascending pathway in the dorsal funiculus in the same location as descending corticospinal axons. EphrinB3/EphA4 signaling is required for guidance of both tracts.