Prolonged Integration of the Adult-Born Axin2 Cell Lineage into Granule Neurons of the Dentate Gyrus

Introduction: The adult hippocampus generates new neurons from radial glia-like neural stem cells. These cells are slowly dividing, or quiescent. After activation they proliferate asymmetrically to generate intermediate progenitor cells, that differentiate further into neuroblasts. These neuroblasts develop into immature neurons and subsequently to mature granule cells that form synaptic connections and become integrated into the hippocampal circuitry. Axin2 is known to be a negative regulator involved in the Wnt/β-catenin pathway and has proved to be a valuable tool in researching the Wnt/β-catenin pathway as it is a prime target for labeling.

Methods: To follow the fate of Axin2-positive cells over time, we performed a time course analysis of granule cells labeled with the tracer tdTomato. Adult mice were induced with tamoxifen and followed over time from one week to six months. Differentiated neurons in the dentate gyrus were counted and normalized per 1000 DAPI-positive nuclei detected with image analysis.

Results: Consistent with previous reports, the Axin2CreERT2 mouse labeled several distinct cell types in the hippocampus, following a single injection of tamoxifen. Our analysis revealed a statistically significant 3-fold increase in the density of Axin2 cells in the animals sacrificed 90 days after tamoxifen injection when compared to other groups. The Axin2-positive granule cell population peaked around 3 months, but subsequently decreased between 3 and 6 months.

Conclusion : In our study, we have characterized the cell fate of the adult-induced Axin2 cell lineage. While others have previously shown that Axin2 expression is active in the hippocampus, our experiments confirm that Axin2 plays a role in the neurogenesis of granule cells of the dentate gyrus in the adult brain. Furthermore, we have demonstrated that Axin2 is present in microvascular endothelia, in line with the recognized function of Wnt/beta catenin signaling in angiogenesis and vascular integrity.