Article ID | Journal | Published Year | Pages | File Type |
---|---|---|---|---|
2199491 | Molecular and Cellular Neuroscience | 2006 | 16 Pages |
Growth factors stimulating neurogenesis act through protein tyrosine kinases which are counterbalanced by protein tyrosine phosphatases (PTPs); thus, downregulation of progenitor PTP function might provide a novel strategy for promoting neurogenesis. We tested the hypotheses that the leukocyte common antigen-related (LAR) PTP is present in adult dentate gyrus progenitors, and that its downregulation would promote neurogenesis. In adult mice, LAR immunostaining was present in Ki-67- and PCNA-positive subgranular zone cells. At 1 h post-BrdU administration, LAR−/− mice demonstrated an ∼3-fold increase in BrdU- and PCNA-positive cells, indicating increased progenitor proliferation. At 1 day and 4 weeks following 6 days of BrdU administration, LAR−/− mice exhibited a significant increase in BrdU and NeuN colabeled cells consistent with increased neurogenesis. In association with increased neurogenesis in LAR−/− mice, stereological analysis revealed a significant 37% increase in the number of neurons present in the granule cell layer. In cultured progenitor clones derived from LAR+/+ mice, LAR immunostaining was present in PCNA- and BrdU-positive cells. Progenitor clones derived from adult LAR−/− hippocampus or LAR+/+ clones made LAR-deficient with LAR siRNA demonstrated increased proliferation and, under differentiation conditions, increased proportions of Tuj1- and MAP2-positive cells. These studies introduce LAR as the first PTP found to be expressed in dentate progenitors and point to inhibition of LAR as a potential strategy for promoting neurogenesis. These findings also provide a rare in vivo demonstration of an association between increased dentate neurogenesis and an expanded population of granule cell layer neurons.