Sonic hedgehog and FGF8 collaborate to induce dopaminergic phenotypes in the Nurr1-overexpressing neural stem cell.
Neural stem cells are self-renewing cells capable of differentiating into all neural lineage cells in vivo and in vitro. In the present study, coordinated induction of midbrain dopaminergic phenotypes in an immortalized multipotent neural stem cell line can be achieved by both overexpression of nuclear receptor Nurr1, and fibroblast growth factor-8 (FGF-8), and sonic hedgehog (Shh) signals. Nurr1 overexpression induces neuronal differentiation and confers competence to respond to extrinsic signals such as Shh and FGF-8 that induce dopaminergic fate in a mouse neural stem cell line. Our findings suggest that immortalized NSCs can serve as an excellent model for understanding mechanisms that regulate specification of ventral midbrain DA neurons and as an unlimited source of DA progenitors for treating Parkinson disease patients by cell replacement.
Kim
Tae Eun
TE
Brain Disease Research Center, Ajou University School of Medicine, Suwon 442-749, Republic of Korea.
Lee
Hack Sup
HS
Lee
Yong Beom
YB
Hong
Seung Hwan
SH
Lee
Young Seek
YS
Ichinose
Hiroshi
H
Kim
Seung U
SU
Lee
Myung Ae
MA
D000818:Animals; D001253:Astrocytes / Q000502:physiology; D002454:Cell Differentiation; D002460:Cell Line; D002461:Cell Line, Transformed; D018920:Coculture Techniques; D004268:DNA-Binding Proteins / Q000235:genetics / Q000378:metabolism*; D004298:Dopamine / Q000096:biosynthesis; D005333:Fetus / Q000166:cytology; D051524:Fibroblast Growth Factor 8; D005346:Fibroblast Growth Factors / Q000494:pharmacology*; D015870:Gene Expression; D053823:Hedgehog Proteins; D006801:Humans; D051379:Mice; D009474:Neurons / Q000166:cytology* / Q000201:enzymology; D057126:Nuclear Receptor Subfamily 4, Group A, Member 2; D010641:Phenotype; D015398:Signal Transduction; D013234:Stem Cells / Q000166:cytology / Q000378:metabolism / Q000502:physiology*; D015534:Trans-Activators / Q000235:genetics / Q000502:physiology*; D014157:Transcription Factors / Q000235:genetics / Q000378:metabolism*; D014162:Transfection; D019076:Transgenes; D014446:Tyrosine 3-Monooxygenase / Q000032:analysis
D004268:DNA-Binding Proteins; C496456:FGF8 protein, human; C496457:Fgf8 protein, mouse; D053823:Hedgehog Proteins; C539882:NR4A2 protein, human; C539883:Nr4a2 protein, mouse; D057126:Nuclear Receptor Subfamily 4, Group A, Member 2; C509239:SHH protein, human; D015534:Trans-Activators; D014157:Transcription Factors; D051524:Fibroblast Growth Factor 8; D005346:Fibroblast Growth Factors; D014446:Tyrosine 3-Monooxygenase; D004298:Dopamine