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Spatial and Mechanical Regulation of EphB Receptor in Neural Stem Cell Function

Abstract

EphB4 receptor tyrosine kinases bind and cluster with membrane bound ephrinB2 ligands on apposing cells to signal juxtacrine. While this signal activation plays a regulatory role in neural stem cell differentiation, the underlying biophysical mechanism remains poorly understood. We reconstituted this juxtacrine signalling geometry between live EphB4-expressing neural stem cells and a supported lipid bilayer presenting laterally mobile monomeric ephrinB2 ligands. A novel method was developed to study neural stem cell differentiation by this hybrid system. This setup allows for observations of the timescale and spatial distribution of receptor-ligand binding and clustering. Furthermore, it accommodates the method of spatial mutation—whereby physical constraints are imposed by lithographically patterned micro-corrals—to restrict EphB4 receptor mobility and precisely control the spatial patterns of receptor-ligand organisation. We found that this physical reorganisation of EphB4-ephrinB2 inhibits neuronal differentiation, suggesting spatial and mechanical sensing of EphB4 signalling in neural stem cells.

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