BMPs signal alternately through a SMAD or FRAP-STAT pathway to regulate fate choice in CNS stem cells.
The ability of stem cells to generate distinct fates is critical for the generation of cellular diversity during development. Central nervous system (CNS) stem cells respond to bone morphogenetic protein (BMP) 4 by differentiating into a wide variety of dorsal CNS and neural crest cell types. We show that distinct mechanisms are responsible for the generation of two of these cell types, smooth muscle and glia. Smooth muscle differentiation requires BMP-mediated Smad1/5/8 activation and predominates where local cell density is low. In contrast, glial differentiation predominates at high local densities in response to BMP4 and is specifically blocked by a dominant-negative mutant Stat3. Upon BMP4 treatment, the serine-threonine kinase FKBP12/rapamycin-associated protein (FRAP), mammalian target of rapamycin (mTOR), associates with Stat3 and facilitates STAT activation. Inhibition of FRAP prevents STAT activation and glial differentiation. Thus, glial differentiation by BMP4 occurs by a novel pathway mediated by FRAP and STAT proteins. These results suggest that a single ligand can regulate cell fate by activating distinct cytoplasmic signals.
Rajan
Prithi
P
Laboratory of Molecular Biology, National Institute of Neurological Disorders and Stroke, National Institutes of Health, Bethesda, MD 20892, USA.
Panchision
David M
DM
Newell
Laura F
LF
McKay
Ronald D G
RD
D000818:Animals; D055415:Bone Morphogenetic Protein 4; D019485:Bone Morphogenetic Proteins / Q000378:metabolism* / Q000494:pharmacology; D002352:Carrier Proteins / Q000378:metabolism*; D002454:Cell Differentiation / Q000187:drug effects / Q000502:physiology*; D019070:Cell Lineage / Q000187:drug effects / Q000502:physiology*; D002478:Cells, Cultured; D002490:Central Nervous System / Q000166:cytology / Q000196:embryology / Q000378:metabolism; D020934:Ciliary Neurotrophic Factor / Q000378:metabolism / Q000494:pharmacology; D004268:DNA-Binding Proteins / Q000235:genetics / Q000378:metabolism*; D005333:Fetus; D051379:Mice; D009130:Muscle, Smooth / Q000166:cytology / Q000196:embryology / Q000378:metabolism; D009432:Neural Crest / Q000166:cytology / Q000196:embryology / Q000378:metabolism; D009457:Neuroglia / Q000166:cytology / Q000378:metabolism; D017933:Peripheral Nervous System / Q000166:cytology / Q000196:embryology / Q000378:metabolism; D017853:Phosphotransferases (Alcohol Group Acceptor); D051381:Rats; D050794:STAT1 Transcription Factor; D050796:STAT3 Transcription Factor; D015398:Signal Transduction / Q000187:drug effects / Q000502:physiology; D020123:Sirolimus / Q000494:pharmacology; D051785:Smad Proteins; D051898:Smad1 Protein; D013234:Stem Cells / Q000166:cytology / Q000187:drug effects / Q000378:metabolism*; D058570:TOR Serine-Threonine Kinases; D015534:Trans-Activators / Q000235:genetics / Q000378:metabolism*
C525810:Bmp4 protein, mouse; C525811:Bmp4 protein, rat; D055415:Bone Morphogenetic Protein 4; D019485:Bone Morphogenetic Proteins; D002352:Carrier Proteins; D020934:Ciliary Neurotrophic Factor; D004268:DNA-Binding Proteins; D050794:STAT1 Transcription Factor; D050796:STAT3 Transcription Factor; D051785:Smad Proteins; D051898:Smad1 Protein; C497401:Smad1 protein, mouse; C497400:Smad1 protein, rat; C494080:Stat1 protein, mouse; C494087:Stat3 protein, mouse; C494088:Stat3 protein, rat; D015534:Trans-Activators; D017853:Phosphotransferases (Alcohol Group Acceptor); C546843:mTOR protein, mouse; C546845:mTOR protein, rat; D058570:TOR Serine-Threonine Kinases; D020123:Sirolimus