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J. Cell Biol. 161 (5): 911-921

Copyright © 2003 by the Rockefeller University Press.


BMPs signal alternately through a SMAD or FRAP–STAT pathway to regulate fate choice in CNS stem cells

Prithi Rajan, David M. Panchision, Laura F. Newell, and Ronald D.G. McKay

Laboratory of Molecular Biology, National Institute of Neurological Disorders and Stroke, National Institutes of Health, Bethesda, MD 20892

Address correspondence to Ronald D.G. McKay, 36 Convent Drive, MSC 4092, Bethesda, MD 20892. Tel.: (301) 496-6574. Fax: (301) 402-1340. E-mail: mckay{at}

Abstract: 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.

Key Words: bone morphogenetic protein; stem cell; SMAD; STAT; mammalian FRAP

P. Rajan and D.M. Panchision contributed equally to this work.

P. Rajan's present address is Psychiatric Genomics, Inc., 19 Firstfield Road, Gaithersburg, MD 20878.

* Abbreviations used in this paper: bFGF, basic FGF; BMP, bone morphogenetic protein; BMPR-IA, BMP receptor type one A; CNS, central nervous system; CNTF, ciliary neurotrophic factor; EMSA, electrophoretic mobility shift assay; FRAP, FKBP12/rapamycin-associated protein; FRB, FKBP12-rapamycin binding; GFAP, glial fibrillary acidic protein; SMA, smooth muscle {alpha}-actin.

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