Thalamic afferents influence cortical progenitors via ephrin A5-EphA4 interactions

Abstract

The phenotype of excitatory cerebral cortex neurons is specified at the progenitor level, orchestrated by various intrinsic and extrinsic factors. Here, we provide evidence for a subcortical contribution to cortical progenitor regulation by thalamic axons via ephrin A5-EphA4 interactions. Ephrin A5 is expressed by thalamic axons and represents a high-affinity ligand for EphA4 receptors detected in cortical precursors. Recombinant ephrin A5-Fc protein, as well as ephrin A ligand-expressing, thalamic axons affect the output of cortical progenitor division in vitro. Ephrin A5-deficient mice show an altered division mode of radial glial cells (RGCs) accompanied by increased numbers of intermediate progenitor cells (IPCs) and an elevated neuronal production for the deep cortical layers at E13.5. In turn, at E16.5 the pool of IPCs is diminished, accompanied by reduced rates of generated neurons destined for the upper cortical layers. This correlates with extended infragranular layers at the expense of superficial cortical layers in adult ephrin A5-deficient and EphA4-deficient mice. We suggest that ephrin A5 ligands imported by invading thalamic axons interact with EphA4-expressing RGCs, thereby contributing to the fine-tuning of IPC generation and thus the proper neuronal output for cortical layers.

Ephrin-A5 regulates inter-male aggression in mice

“…These observations are consistent with our previous findings that inactivation of EphA5, a receptor of ephrin-A5, also reduced inter-male aggression [23], suggesting that ephrin-A5/EphA5 signaling modulates neural pathways in brain regions that control aggression. Ephrin-A5 has been shown to regulate neural progenitor cell production [67], interneuron migration [68] and neuronal dendritic arborization [69]. Future studies will reveal which specific functions are required for the regulation of aggressive behavior.…”

Decreased maternal behavior and anxiety in ephrin‐A5−/− mice

“…Thus, it is possible that the decreased maternal behavior seen in the null mice is due to alteration in the mesolimbic DA system. However, since ephrin-A5 is expressed broadly in the brain (Deschamps et al , 2009, Gao et al , 1998), and has been shown to regulate neurogenesis (Depaepe et al , 2005, Gerstmann et al , 2015, Noh & Park, 2015, Shu et al , 2016), and formation of several other neural circuits (Carvalho et al , 2006, Guellmar et al , 2009, Steinecke et al , 2014, Tadesse et al , 2013, Yates et al , 2014) the precise mechanism underlying maternal care deficiency remains to be determined by future investigations. Thus, the mechanistic connection of ephrin-A5 function to maternal behavior is at present unclear, and this gene may not regulate maternal care exclusively.…”

A dual-strategy expression screen for candidate connectivity labels in the developing thalamus

“…The most extensively investigated have been EphA4 , EphA7 , EphrinA2 ( Efna2 ) and EphrinA5 ( Efna5 ). Roles for these genes have been demonstrated in parcellation of thalamic nuclei [19], target selection and topography of retinal axons into the thalamus [40], topographic guidance of thalamic axons through the ventral telencephalon [41], areal and layer-specific targeting and topography (reviewed in [42]), reciprocal corticothalamic axon guidance and target selection [43, 44] and even influences on cortical progenitor proliferation and differentiation dynamics [45]. EphB1 and - B2 have also recently been shown to mediate thalamic axon guidance through the ventral telencephalon [46].…”