Multiple roles of ephrins during the formation of thalamocortical projections: Maps and more

Abstract

The functional architecture of the cerebral cortex is based on intrinsic connections that precisely link neurons from distinct cortical laminae as well as layer-specific afferent and efferent projections. Experimental strategies using in vitro assays originally developed by Friedrich Bonhoeffer have suggested that positional cues confined to individual layers regulate the assembly of local cortical circuits and the formation of thalamocortical projections. One of these wiring molecules is ephrinA5, a ligand for Eph receptor tyrosine kinases. EphrinA5 and Eph receptors exhibit highly dynamic expression patterns in distinct regions of the cortex and thalamus during early and late stages of thalamocortical and cortical circuit formation. In vitro assays suggest that ephrinA5 is a multifunctional wiring molecule for different populations of cortical and thalamic axons. Additionally, the expression patterns of ephrinA5 during cortical development are consistent with this molecule regulating, in alternative ways, specific components of thalamic and cortical connectivity. To test this directly, the organization of thalamocortical projections was examined in mice lacking ephrinA5 gene expression. The anatomical studies in ephrinA5 knockout animals revealed a miswiring of limbic thalamic projections and changes in neocortical circuits that were predicted from the expression pattern and the in vitro analysis of ephrinA5 function.

EphrinA5 protein distribution in the developing mouse brain

“…We found a particularly strong signal at E16.5 in the primitive primary somatosensory cortex (S1), when thalamic axons reach the subplate zone. This is consistent with the presence of ephrinA5 mRNA in the subplate and cortical plate of S1 at this stage [22-24,27]. Indeed, ephrinA5 is thought to interact with and repulse ventrobasal thalamic terminal arbors expressing EphA4, and to be responsible for the precise topographic mapping of thalamic afferents into S1 [24].…”

“…Previous studies showed different patterns of ephrinA5 mRNA expression, depending of the thalamic nuclei and the stage observed: at E13.5, Bolz et al [27] described a weak mRNA expression in the ventricular zone of the dorsal thalamus at the caudal level with no detectable expression in the mid- or rostral levels of the dorsal thalamus. Feldheim et al [10] described ephrinA5 mRNA expression from E14.5, in the dorsal and ventral lateral geniculate nuclei in a ventral, lateral and anterior (high) to dorsal, medial and posterior (low) gradient.…”

“…Feldheim et al [10] described ephrinA5 mRNA expression from E14.5, in the dorsal and ventral lateral geniculate nuclei in a ventral, lateral and anterior (high) to dorsal, medial and posterior (low) gradient. Between E16.5 and E18.5, nuclei of the lateral part of the dorsal thalamus [27] and ventral nuclei [29] both exhibit ephrinA5 mRNA. Our results partially match with these previous studies, as we showed here that ephrinA5 protein was strongly expressed in the thalamus in a ventral and rostral (high) to dorsal and caudal (low) gradient especially from E12.5 to E16.5.…”

“…The study of its expression, mainly explored at the mRNA level in the rodent developing brain, has shown that ephrinA5 is present from early organogenesis [16] to postnatal stages throughout the central nervous system. In the telencephalon, ephrinA5 mRNA is expressed in the olfactory system [17,18], in the lateral and medial ganglionic eminences and their ventricular zones [19-21] and in the cortex [22-27]. EphrinA5 transcript expression has been also detected in the diencephalon (hypothalamus and thalamus) [10,21,27-29] and in the inferior and superior colliculi as well as in the pretectal nuclei and the red nucleus of the mesencephalon [28,30,10,21].…”

EphrinA5 acts as a tumor suppressor in glioma by negative regulation of epidermal growth factor receptor

“…A majority of earlier studies focused on the role of ephrinA5 in developmental biology, especially the nervous system (Bolz et al, 2004;Otal et al, 2006). Recently, the role of ephrinA5 in cancer has gained attention, and the expression pattern of ephrinA5 has been examined in several types of cancers, such as ovarian cancer (Herath et al, 2006) and osteosarcoma (Varelias et al, 2002).…”