Altered differentiation of neural stem cells in fragile X syndrome.
Fragile X syndrome, a common form of inherited mental retardation, is caused by the absence of the fragile X mental retardation protein (FMRP) due to a mutation in the FMR1 gene. We investigated the differentiation of neural stem cells generated from the brains of fmr1-knockout (KO) mice and from postmortem tissue of a fragile X fetus. Mouse and human FMRP-deficient neurospheres generated more TuJ1-positive cells (3-fold and 5-fold, respectively) than the control neurospheres generated from normal mouse and human brains, and these cells showed morphological alterations with fewer and shorter neurites and a smaller cell body volume. The number of cells expressing glial fibrillary acidic protein and generated by these neurospheres was reduced because of increased apoptotic cell death. Furthermore, there was an increase in a population of cells with intense oscillatory Ca2+ responses to neurotransmitters in differentiated cells lacking FMRP. In addition, the number of cells in a cohort of bromodeoxyuridine-labeled newborn cells was increased in the subventricular zone of the telencephalon of the fmr1-KO mouse in vivo. These results demonstrate substantial alterations in the early maturation of FMRP-deficient neural stem cells in fragile X syndrome and in the fmr1-KO mice.
Castrén
Maija
M
Neuroscience Center, University of Helsinki, P.O. Box 56, 00014 Helsinki, Finland. maija.castren@helsinki.fi
Tervonen
Topi
T
Kärkkäinen
Virve
V
Heinonen
Seppo
S
Castrén
Eero
E
Larsson
Kim
K
Bakker
Cathy E
CE
Oostra
Ben A
BA
Akerman
Karl
K
D000818:Animals; D002118:Calcium / Q000494:pharmacology; D002454:Cell Differentiation / Q000187:drug effects; D002478:Cells, Cultured; D051860:Fragile X Messenger Ribonucleoprotein 1 / Q000235:genetics / Q000378:metabolism; D005600:Fragile X Syndrome / Q000235:genetics / Q000378:metabolism / Q000473:pathology*; D051379:Mice; D018345:Mice, Knockout; D009474:Neurons / Q000187:drug effects / Q000378:metabolism / Q000473:pathology*; D013234:Stem Cells / Q000187:drug effects / Q000378:metabolism / Q000473:pathology*
D002118:Calcium; D051860:Fragile X Messenger Ribonucleoprotein 1; C497684:Fmr1 protein, mouse