Downregulation of the LAR protein tyrosine phosphatase receptor is associated with increased dentate gyrus neurogenesis and an increased number of granule cell layer neurons

BERNABEU, R, YANG, T, XIE, Y, MEHTA, B, MA, YM, AND LONGO, M

MOLECULAR AND CELLULAR NEUROSCIENCES.

ACADEMIC PRESS INC ELSEVIER SCIENCE

Año: 2006 vol. 31 p. 723 - 738

1044-7431

Growth factors stimulating neurogenesis act through protein tyrosinekinases which are counterbalanced by protein tyrosine phosphatases(PTPs); thus, downregulation of progenitor PTP function mightprovide a novel strategy for promoting neurogenesis. We tested thehypotheses that the leukocyte common antigen-related (LAR) PTP ispresent in adult dentate gyrus progenitors, and that its downregulationwould promote neurogenesis. In adult mice, LAR immunostaining waspresent in Ki-67- and PCNA-positive subgranular zone cells. At 1h post-BrdU administration, LAR/ mice demonstrated an ¨3-foldincrease in BrdU- and PCNA-positive cells, indicating increasedprogenitor proliferation. At 1 day and 4 weeks following 6 days ofBrdU administration, LAR/ mice exhibited a significant increase inBrdU and NeuN colabeled cells consistent with increased neurogenesis.In association with increased neurogenesis in LAR/ mice, stereologicalanalysis revealed a significant 37% increase in the number ofneurons present in the granule cell layer. In cultured progenitor clonesderived from LAR+/+ mice, LAR immunostaining was present inPCNA- and BrdU-positive cells. Progenitor clones derived from adultLAR/ hippocampus or LAR+/+ clones made LAR-deficient withLAR siRNA demonstrated increased proliferation and, under differentiationconditions, increased proportions of Tuj1- and MAP2-positivecells. These studies introduce LAR as the first PTP found to beexpressed in dentate progenitors and point to inhibition of LAR as apotential strategy for promoting neurogenesis. These findings alsoprovide a rare in vivo demonstration of an association betweenincreased dentate neurogenesis and an expanded population of granulecell layer neurons.