Regulation of thalamic neurite outgrowth by the Eph ligand ephrin-A5: implications in the development of thalamocortical projections.

The cerebral cortex is parcellated into different functional domains that receive distinct inputs from other cortical and subcortical regions. The molecular mechanisms underlying the specificity of connections of cortical afferents remain unclear. We report here that the Eph family tyrosine kinase receptor EphA5 and the ligand ephrin-A5 may play a key role in the exclusion of the limbic thalamic afferents from the sensorimotor cortex by mediating repulsive interactions. In situ hybridization shows that the EphA5 transcript is expressed at high levels in both cortical and subcortical limbic regions, including the frontal cortex, the subiculum, and the medial thalamic nuclei. In contrast, ephrin-A5 is transcribed abundantly in the sensorimotor cortex. Consistent with the complementary expression, the ligand inhibited dramatically the growth of neurites from neurons isolated from the medial thalamus but was permissive for the growth of neurites from lateral thalamic neurons, which is primarily nonlimbic. Similarly, the growth of neurites from Eph-A5-expressing neurons isolated from the subiculum was inhibited by ephrin-A5. Our studies suggest that the Eph family ligand ephrin-A5 serves as a general inhibitor of axonal growth from limbic neurons, which may serve to prevent innervation of inappropriate primary sensorimotor regions, thus contributing to the generation of specificity of thalamic cortical afferents.