Polysialic acid regulates the clustering, migration, and neuronal differentiation of progenitor cells in the adult hippocampus.
Newborn cells of the adult dentate gyrus in the hippocampus are characterized by their abundant expression of polysialic acid (PSA), a carbohydrate attached to the neural cell adhesion molecule (NCAM). PSA+ newborn cells of the dentate gyrus form clusters with proliferating neural progenitor cells, migrate away from these clusters, and terminally differentiate. To identify the roles of PSA in the development of adult progenitors of the dentate gyrus, we injected endoneuraminidase N (endoN) into the hippocampus of adult rats to specifically cleave PSA from NCAM. Two days later, we administered the mitotic marker, 5-bromo-2'-deoxyuridine (BrdU). Three days after BrdU injection, BrdU+ cells were found inside and outside the clusters of newborn cells. In endoN-treated animals, the total number of BrdU+ cells was not changed but significantly more BrdU+ cells were present within clusters, suggesting that PSA normally facilitates the migration of progenitors away from the clusters. Seven days post-BrdU injection, endoN-treated animals had significantly more BrdU+ cells which were also positive for the mature neuronal nuclear marker NeuN compared with controls, indicating that the loss of PSA from progenitor cells increases neuronal differentiation. This report is the first demonstration that PSA is involved in controlling the spatio-temporal neuronal maturation of adult hippocampal progenitors in the normal brain. In vitro, the removal of PSA from adult-derived neural progenitors significantly enhanced neuronal differentiation, strengthening our in vivo findings and indicating that PSA removal on isolated progenitor cells, apart from a complex in vivo environment, induces neuronal maturation.
Department of Laboratory Medicine and Pathobiology, University of Toronto, Ontario, Canada M5G 1L9.
Alison
A
Burgess
Steven R
SR
Wainwright
Lamya S
LS
Shihabuddin
Urs
U
Rutishauser
Tatsunori
T
Seki
Isabelle
I
Aubert
D053687:Adult Stem Cells / Q000187:drug effects*; D000704:Analysis of Variance; D000818:Animals; D001973:Bromodeoxyuridine / Q000378:metabolism; D002452:Cell Count; D002454:Cell Differentiation / Q000187:drug effects*; D002465:Cell Movement / Q000187:drug effects / Q000502:physiology*; D000089622:Doublecortin Domain Proteins; D004815:Epidermal Growth Factor / Q000494:pharmacology; D005346:Fibroblast Growth Factors / Q000494:pharmacology; D006026:Glycoside Hydrolases / Q000494:pharmacology; D006624:Hippocampus / Q000166:cytology*; D019394:Ki-67 Antigen / Q000378:metabolism; D026901:Membrane Transport Proteins / Q000378:metabolism; D018613:Microscopy, Confocal; D008869:Microtubule-Associated Proteins / Q000378:metabolism; D027501:Monocarboxylic Acid Transporters; D009474:Neurons / Q000187:drug effects / Q000502:physiology*; D009479:Neuropeptides / Q000378:metabolism; D010751:Phosphopyruvate Hydratase / Q000378:metabolism; D051381:Rats; D017208:Rats, Wistar; D012794:Sialic Acids / Q000378:metabolism*
D000089622:Doublecortin Domain Proteins; D019394:Ki-67 Antigen; C489787:MAP2 protein, rat; D026901:Membrane Transport Proteins; D008869:Microtubule-Associated Proteins; D027501:Monocarboxylic Acid Transporters; D009479:Neuropeptides; D012794:Sialic Acids; C021319:polysialic acid; D005346:Fibroblast Growth Factors; D004815:Epidermal Growth Factor; D006026:Glycoside Hydrolases; C090534:endo-alpha-sialidase; D010751:Phosphopyruvate Hydratase; D001973:Bromodeoxyuridine