Part VI: Dissecting Cell Signaling Networks That Regulate Adult Neural Stem Cell Functions

In the adult mammalian hippocampus, neurogenesis (in which new neurons are generated and integrated into the CNS) is believed to underlie learning and memory. Within the hippocampus, numerous cell types communicate via diverse signals. Some of these signals control neural stem and progenitor cells (NSPCs), which can divide or terminally differentiate into neurons, astrocytes, or oligodendrocytes, and then migrate and integrate into the existing brain circuitry. I have identified novel functions for a ligand-receptor pair, ephrin-A4 and EphA4, in this process. NSPCs express the receptor EphA4, while ephrin-A4 is predominately expressed by mature neurons. In cell culture studies, treating adult NSPCs with ephrin-A4 activated EphA4 and induced neuronal differentiation, and blocking EphA4 ligand-binding with an antagonist reversed these effects. Ephrin-A4/EphA4 signaling also regulated the migration of NSPCs. Finally, using AAV to deliver CRISPR/Cas9 into the brains of adult mice, I found that knocking out EphA4 or ephrin-A4 in select cell types alters neuronal differentiation and migration in vivo. These data thus support a significant role for ephrin-A4/EphA4 signaling in regulating adult neurogenesis.