tPA regulates neurite outgrowth by phosphorylation of LRP5/6 in neural progenitor cells.
Despite the important role of tissue plasminogen activator (tPA) as a neuromodulator in neurons, microglia, and astrocytes, its role in neural progenitor cell (NPC) development is not clear yet. We identified that tPA is highly expressed in NPCs compared with neurons. Inhibition of tPA activity or expression using tPA stop, PAI-1, or tPA siRNA inhibited neurite outgrowth from NPCs, while overexpression or addition of exogenous tPA increased neurite outgrowth. The expression of Wnt and β-catenin as well as phosphorylation of LRP5 and LRP6, which has been implicated in Wnt-β-catenin signaling, was rapidly increased after tPA treatment and was decreased by tPA siRNA transfection. Knockdown of β-catenin or LRP5/6 expression by siRNA prevented tPA-induced neurite extension. NPCs obtained from tPA KO mice showed impaired neurite outgrowth compared with WT NPCs. In ischemic rat brains, axon density was higher in the brains transplanted with WT NPCs than in those with tPA KO NPCs, suggesting increased axonal sprouting by NPC-derived tPA. tPA-mediated regulation of neuronal maturation in NPCs may play an important role during development and in regenerative conditions.
Department of Neuroscience, School of Medicine and Center for Neuroscience Research, IBST, Konkuk University, Hwayang-dong, Gwangjin-gu, Seoul, 143-701, Republic of Korea.
Sung Hoon
SH
Lee
Hyun Myung
HM
Ko
Kyoung Ja
KJ
Kwon
Jongmin
J
Lee
Seol-Heui
SH
Han
Dong Wook
DW
Han
Jae Hoon
JH
Cheong
Jong Hoon
JH
Ryu
Chan Young
CY
Shin
D000818:Animals; D002478:Cells, Cultured; D060492:Low Density Lipoprotein Receptor-Related Protein-5 / Q000235:genetics / Q000378:metabolism*; D060488:Low Density Lipoprotein Receptor-Related Protein-6 / Q000235:genetics / Q000378:metabolism*; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D058953:Neural Stem Cells / Q000502:physiology*; D016501:Neurites / Q000187:drug effects / Q000378:metabolism*; D055495:Neurogenesis / Q000502:physiology*; D010766:Phosphorylation / Q000502:physiology; D034741:RNA, Small Interfering / Q000235:genetics; D051381:Rats; D017207:Rats, Sprague-Dawley; D010959:Tissue Plasminogen Activator / Q000502:physiology*
D060492:Low Density Lipoprotein Receptor-Related Protein-5; D060488:Low Density Lipoprotein Receptor-Related Protein-6; C555484:Lrp5 protein, rat; C555477:Lrp6 protein, rat; D034741:RNA, Small Interfering; D010959:Tissue Plasminogen Activator