Bone morphogenetic protein 4 stimulates attachment of neurospheres and astrogenesis of neural stem cells in neurospheres via phosphatidylinositol 3 kinase-mediated upregulation of N-cadherin.
The neurosphere culture system is useful for expanding neural stem cells (NSCs) without affecting self-renewal potential and multipotency. However, the extrinsic signals that affect the formation or dissociation of neurospheres are poorly understood. Here, we found that bone morphogenetic protein 4 (BMP4) induced the attachment of neurospheres, astrocytic differentiation, and migration of neurosphere NSCs. These outcomes were accompanied by Akt activation and upregulation of the adhesion molecule, N-cadherin. A phosphatidylinositol 3 kinase (PI3 kinase) inhibitor (LY294002) blocked attachment of neurosphere, astrocytic differentiation, migration, and N-cadherin upregulation of neurosphre NSCs. The PI3 kinase-Akt pathway appeared to selectively mediate the effects of BMP4, as neurosphere attachment was unaffected by MEK inhibitors (PD98059 and U0126). Importantly, a neutralizing N-cadherin antibody inhibited BMP4-induced neurosphere attachment, astrocytic differentiation, and migration of neurosphere NSCs. Together, these findings show that BMP4-induced attachment of neurospheres is related to the astrocytic differentiation of these cells and that these effects are attributable, at least in part, to PI3 kinase-Akt pathway-dependent induction of N-cadherin.
Kim
M Y
MY
Translational Research Center for Protein Function Control, College of Life Science and Biotechnology, Yonsei University, Seoul 120-749, Korea.
Kaduwal
S
S
Yang
D H
DH
Choi
K Y
KY
D000818:Animals; D001253:Astrocytes / Q000166:cytology / Q000201:enzymology / Q000502:physiology*; D055415:Bone Morphogenetic Protein 4 / Q000502:physiology*; D015820:Cadherins / Q000096:biosynthesis*; D002448:Cell Adhesion / Q000502:physiology; D002478:Cells, Cultured; D004789:Enzyme Activation / Q000502:physiology; D058953:Neural Stem Cells / Q000201:enzymology / Q000502:physiology*; D055495:Neurogenesis / Q000502:physiology; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism / Q000502:physiology*; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley; D015398:Signal Transduction / Q000502:physiology; D015854:Up-Regulation / Q000502:physiology*
C525811:Bmp4 protein, rat; D055415:Bone Morphogenetic Protein 4; D015820:Cadherins; D019869:Phosphatidylinositol 3-Kinases; D051057:Proto-Oncogene Proteins c-akt