EPH-B and Ephrin-B Signaling in Migration and Proliferation of Stem Cells
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In this dissertation, I investigate the role of Eph-ephrin signaling in the Dentate Gyrus (DG). The DG is a distinctive neuronal structure located in the hippocampus and is one of two areas in the mature brain where stem and progenitor cells reside to continuously produce new neurons throughout adulthood. While Eph-ephrin signaling has been linked to other stem cell populations in the adult, involvement in the progenitor population residing in the hippocampus had not been demonstrated. Here, I establish the expression of B subclass Eph receptors in both embryonic and adult progenitors in the hippocampus. Analysis of EphB1 -/-mutant mice shows that this receptor tyrosine kinase is involved in the regulation of proliferation and polarity of progenitor cells in the neurogenic niche of the DG. Ephrin-B3 acts as a ligand to regulate some aspects of EphB1 activity in the DG. I also show that the EphB2 receptor tyrosine kinase is critical for normal formation of a specific region of the DG known as the lateral suprapyramidal blade (LSB) during late embryonic and early postnatal development. Analysis of intracellular truncation and single amino acid point mutations demonstrates that the tyrosine kinase catalytic activity of EphB2 is essential for LSB formation. This activity is consistent with specific expression of EphB2 in the neural progenitor cells that migrate in a medial direction from the dentate notch of the lateral ventricles to populate and form the DG near the midline of the brain. I further show that ephrin-B1 alone acts as the ligand to activate EphB2 forward signaling in these migrating neural progenitors to contribute to the formation of this vitally important structure. Finally I briefly describe the role of EphB2 forward signaling in stem cell populations beyond the hippocampus. This data demonstrates that Eph-ephrin signaling is intimately involved in both the formation of the neurogenic niche and in the regulation of progenitor cells that occupy that niche.