BMP and FGF regulate the development of EGF-responsive neural progenitor cells.
Temporal changes in progenitor cell responses to extrinsic signals play an important role in development, but little is known about the mechanisms that determine how these changes occur. In the rodent CNS, expression of epidermal growth factor receptors (EGFRs) increases during embryonic development, conferring mitotic responsiveness to EGF among multipotent stem cells. Here we show that cell-cell signaling controls this change. Whereas EGF-responsive stem cells develop on schedule in explant and aggregate cultures of embryonic cortex, co-culture with younger cortical cells delays their development. Exogenous BMP4 mimics the effect of younger cells, reversibly inhibiting changes in EGFR expression and responsiveness. Moreover, blocking endogenous BMP receptors in progenitors with a virus transducing dnBMPR1B accelerates changes in EGFR signaling. This involves a non-cell-autonomous mechanism, suggesting that BMP negatively regulates signal(s) that promote the development of EGF-responsive stem cells. FGF2 is a good candidate for such a signal, as we find that it antagonizes the inhibitory effects of younger cortical cells and exogenous BMP4. These findings suggest that a balance between antagonistic extrinsic signals regulates temporal changes in an intrinsic property of neural progenitor cells.
Lillien
L
L
Department of Neurobiology and Pittsburgh Cancer Institute, University of Pittsburgh School of Medicine, W1454 Biomedical Science Tower, Pittsburgh, PA 15261, USA. lillien+@pitt.edu
Raphael
H
H
D000818:Animals; D055415:Bone Morphogenetic Protein 4; D052004:Bone Morphogenetic Protein Receptors; D019485:Bone Morphogenetic Proteins / Q000378:metabolism* / Q000494:pharmacology; D002454:Cell Differentiation / Q000187:drug effects; D002490:Central Nervous System / Q000187:drug effects / Q000196:embryology* / Q000378:metabolism*; D066246:ErbB Receptors / Q000378:metabolism*; D005260:Female; D005346:Fibroblast Growth Factors / Q000378:metabolism*; D005865:Gestational Age; D011247:Pregnancy; D051381:Rats; D017207:Rats, Sprague-Dawley; D011956:Receptors, Cell Surface / Q000378:metabolism; D017978:Receptors, Growth Factor; D015398:Signal Transduction; D013234:Stem Cells / Q000166:cytology / Q000187:drug effects
C525811:Bmp4 protein, rat; D055415:Bone Morphogenetic Protein 4; D019485:Bone Morphogenetic Proteins; D011956:Receptors, Cell Surface; D017978:Receptors, Growth Factor; D005346:Fibroblast Growth Factors; D066246:ErbB Receptors; D052004:Bone Morphogenetic Protein Receptors