Tissue plasminogen activator contributes to alterations of neuronal migration and activity-dependent responses in fragile X mice.
Fragile X syndrome (FXS) is the most common inherited neurodevelopmental disorder with intellectual disability. Here, we show that the expression of tissue plasminogen activator (tPA) is increased in glial cells differentiated from neural progenitors of Fmr1 knock-out mice, a mouse model for FXS, and that tPA is involved in the altered migration and differentiation of these progenitors lacking FMR1 protein (FMRP). When tPA function is blocked with an antibody, enhanced migration of doublecortin-immunoreactive neurons in 1 d differentiated FMRP-deficient neurospheres is normalized. In time-lapse imaging, blocking the tPA function promotes early glial differentiation and reduces the velocity of nuclear movement of FMRP-deficient radial glia. In addition, we show that enhanced intracellular Ca(2+) responses to depolarization with potassium are prevented by the treatment with the tPA-neutralizing antibody in FMRP-deficient cells during early neural progenitor differentiation. Alterations of the tPA expression in the embryonic, postnatal, and adult brain of Fmr1 knock-out mice suggest an important role for tPA in the abnormal neuronal differentiation and plasticity in FXS. Altogether, the results indicate that tPA may prove to be an interesting potential target for pharmacological intervention in FXS.
Institute of Biomedicine/Physiology, University of Helsinki, FIN-00014 Helsinki, and Division of Child Neurology, Hospital for Children and Adolescents, Helsinki University Central Hospital, 00029 HUS, Finland.
V Swaroop
VS
Achuta
Veronika
V
Rezov
Marko
M
Uutela
Verna
V
Louhivuori
Lauri
L
Louhivuori
Maija L
ML
Castrén
D000818:Animals; D000831:Animals, Newborn; D002118:Calcium / Q000378:metabolism; D002465:Cell Movement / Q000187:drug effects / Q000235:genetics*; D002478:Cells, Cultured; D004195:Disease Models, Animal; D000089622:Doublecortin Domain Proteins; D004622:Embryo, Mammalian; D000071438:Fatty Acid-Binding Protein 7; D050556:Fatty Acid-Binding Proteins / Q000378:metabolism; D005260:Female; D005343:Fibrinolytic Agents / Q000494:pharmacology*; D051860:Fragile X Messenger Ribonucleoprotein 1 / Q000235:genetics / Q000378:metabolism; D005600:Fragile X Syndrome / Q000235:genetics / Q000473:pathology*; D018507:Gene Expression Regulation, Developmental / Q000235:genetics / Q000502:physiology*; D005904:Glial Fibrillary Acidic Protein / Q000378:metabolism; D006801:Humans; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008869:Microtubule-Associated Proteins / Q000378:metabolism; D009419:Nerve Tissue Proteins / Q000378:metabolism; D058953:Neural Stem Cells / Q000378:metabolism; D009474:Neurons / Q000187:drug effects / Q000502:physiology*; D009479:Neuropeptides / Q000378:metabolism; D017395:Plasminogen Activator Inhibitor 1 / Q000378:metabolism; D011247:Pregnancy; D010959:Tissue Plasminogen Activator / Q000378:metabolism*
D002118:Calcium; D000089622:Doublecortin Domain Proteins; D000071438:Fatty Acid-Binding Protein 7; D050556:Fatty Acid-Binding Proteins; D005343:Fibrinolytic Agents; D051860:Fragile X Messenger Ribonucleoprotein 1; D005904:Glial Fibrillary Acidic Protein; D008869:Microtubule-Associated Proteins; D009419:Nerve Tissue Proteins; D009479:Neuropeptides; D017395:Plasminogen Activator Inhibitor 1; D010959:Tissue Plasminogen Activator; C086936:Fabp7 protein, mouse; C497684:Fmr1 protein, mouse
FMRP; depolarization; differentiation; glia; neurons; stem cells