Downregulation of the LAR protein tyrosine phosphatase receptor is associated with increased dentate gyrus neurogenesis and an increased number of granule cell layer neurons.
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 approximately 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.
UNC School of Medicine, Department of Neurology CB7025, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA.
Ramon
R
Bernabeu
Tao
T
Yang
Youmei
Y
Xie
Brijesh
B
Mehta
Shuang Yong
SY
Ma
Frank M
FM
Longo
D000818:Animals; D015415:Biomarkers / Q000378:metabolism; D049109:Cell Proliferation; D002478:Cells, Cultured; D018891:Dentate Gyrus / Q000166:cytology / Q000502:physiology*; D015536:Down-Regulation; D006624:Hippocampus / Q000166:cytology*; D019394:Ki-67 Antigen / Q000378:metabolism; D051379:Mice; D018345:Mice, Knockout; D009419:Nerve Tissue Proteins / Q000235:genetics / Q000378:metabolism*; D009474:Neurons / Q000166:cytology / Q000502:physiology*; D010641:Phenotype; D018809:Proliferating Cell Nuclear Antigen / Q000378:metabolism; D017027:Protein Tyrosine Phosphatases / Q000235:genetics / Q000378:metabolism*; D034741:RNA, Small Interfering / Q000235:genetics / Q000378:metabolism; D054623:Receptor-Like Protein Tyrosine Phosphatases, Class 2; D011956:Receptors, Cell Surface / Q000235:genetics / Q000378:metabolism*; D011993:Recombinant Fusion Proteins / Q000235:genetics / Q000378:metabolism; D013234:Stem Cells / Q000166:cytology / Q000502:physiology
D015415:Biomarkers; D019394:Ki-67 Antigen; D009419:Nerve Tissue Proteins; D018809:Proliferating Cell Nuclear Antigen; D034741:RNA, Small Interfering; D011956:Receptors, Cell Surface; D011993:Recombinant Fusion Proteins; D017027:Protein Tyrosine Phosphatases; C000709129:Ptprf protein, mouse; D054623:Receptor-Like Protein Tyrosine Phosphatases, Class 2