Ephrin‐A4 inhibits sensory neurite outgrowth and is regulated by neonatal skin wounding

Abstract

The mechanisms for directing and organising sensory axons within developing skin remain largely unknown. The present study provides the first evidence that signalling occurs between A-ephrins and Eph-A receptors during the development of rat cutaneous sensory innervation both during normal development and following skin injury. Specifically, our data indicate that ephrin-A4 mRNA and protein are expressed in the epidermis during late embryogenesis and the early postnatal period (E16-P3), and expression is significantly down-regulated postnatally. In addition, Eph-A receptors are expressed on dorsal root ganglia (DRG) cells at birth. The pattern of ephrin-A4 expression is mirrored by epidermal innervation, so that sensory terminals are restricted to epidermal regions devoid of ephrin-A4 but increase as ephrin-A4 expression subsides postnatally. Neonatal skin wounding causes sensory hyperinnervation and a differential screen of wounded vs. nonwounded skin revealed down-regulation of epidermal ephrin-A4 following neonatal skin wounding. Expression studies showed that this down-regulation is below the wound and coincides exactly with the onset of hyperinnervation. In vitro experiments show a function for ephrin-A4-Fc in inhibiting rat DRG neuronal growth and guidance when presented as either substratum-bound stripes of ephrin-A4-Fc or as soluble clustered proteins. In conclusion, these observations suggest that the Eph family ligand ephrin-A4 has an inhibitory influence on neonatal cutaneous nerve terminals from DRG sensory neurons in the hindlimb, and may serve to prevent inappropriate innervation of cutaneous regions. In addition, the absence of ephrin-A4 following neonatal skin wounding may play a critical permissive role in the sprouting response.

An impaired transendothelial migration potential of chronic lymphocytic leukemia (CLL) cells can be linked to ephrin-A4 expression

“…Accordingly, the EphA2-Fc treatment of CLL cells diminishes the proportion of cell conjugates established between them and HUVECs in an EFNA4 expression-dependent manner. EFNA4 reverse signaling has been reported to act through repulsive signals in other systems like inhibiting sensory neurite outgrowth within the developing mouse skin, 30 further suggesting that this molecule can lead to repulsive signals during cell-cell contacts in the TEM process.…”

Nogo Receptor Homolog NgR2 Expressed in Sensory DRG Neurons Controls Epidermal Innervation by Interaction with Versican

“…In addition, we do not know the actual levels of NgR2 receptor proteins on DRG axons from different subclasses, so it is unclear whether this phenotype results from a reduced NgR2 surface expression or from a lack of potential coreceptors required for NgR2-signaling. The NgR receptor complex contains both, the NgR and either the neurotrophin receptor p75 NTR or the orphan receptor TNF family member TROY (Mironova and Giger, 2013), but the functional signaling partner for NgR2 in sensory DRG neurons is currently unknown. A recent study suggests that NgR2 associates with TROY to limit synapse formation of hippocampal neurons in vitro (Wills et al, 2012).…”

Connexin 43 stabilizes astrocytes in a stroke-like milieu to facilitate neuronal recovery

“…The binding of ligands (ie, Ephrin-A1, Ephrin-A3, Ephrin-A4, Ephrin-A5) is the premise for the inhibitory effect of EphA4. Moreover, it was found that Ephrin-A4 inhibited neurite growth in the peripheral nervous system [5] . Inhibiting and reversing the activation of astrocytes appears to be rational and practical.…”