Regulation of neural stem cell differentiation in the forebrain.
In the developing forebrain, mounting evidence suggests that neural stem cell proliferation and differentiation is regulated by growth factors. In vitro in the presence of serum, stem cell proliferation is predominantly mediated by fibroblast growth factor-2 (FGF-2) whereas neuronal differentiation can be triggered by FGF-1 in association with a specific heparan sulphate proteoglycan. On the other hand, astrocyte differentiation in vivo and in vitro appears to be dependent on signalling through the leukaemia inhibitory factor receptor (LIFR). The evidence suggests that in the absence of LIFR signalling, the stem cell population is present at approximately the same frequency and can generate neurons but is blocked from producing astrocytes that express glial fibrillary acidic protein (GFAP) or have trophic functions. The block can be overcome by other growth factors such as BMP-2/4 or interferon-gamma, providing further evidence that the inhibition to astrocyte development does not result from loss of a precursor population. Signalling through the LIFR, in addition to stimulating astrocyte differentiation, may also inhibit neuronal differentiation, which may explain why this receptor is expressed at the earliest stages of neurogenesis. Another signalling system which also exerts its influence on neurogenesis through active inhibition is Delta-Notch. We show in vitro that at high cell densities which impede neuronal production by FGF-1, lowering the levels of expression of the receptor Notch by antisense oligonucleotide results in a significant increase in neuronal production. Thus, stem cell differentiation appears to be dependent on the outcome of interactions between a number of signalling pathways, some which promote specific lineages and some which inhibit.
Bartlett
P F
PF
Walter and Eliza Hall Institute of Medical Research, Parkville, Victoria, Australia. bartlett@wehi.edu.au
Brooker
G J
GJ
Faux
C H
CH
Dutton
R
R
Murphy
M
M
Turnley
A
A
Kilpatrick
T J
TJ
D000818:Animals; D001253:Astrocytes / Q000166:cytology; D055396:Bone Morphogenetic Protein 2; D055415:Bone Morphogenetic Protein 4; D019485:Bone Morphogenetic Proteins / Q000502:physiology; D002454:Cell Differentiation; D005346:Fibroblast Growth Factors / Q000502:physiology; D005904:Glial Fibrillary Acidic Protein / Q000502:physiology; D006131:Growth Inhibitors; D007371:Interferon-gamma / Q000502:physiology; D015850:Interleukin-6; D053605:Leukemia Inhibitory Factor; D053680:Leukemia Inhibitory Factor Receptor alpha Subunit; D008222:Lymphokines; D051379:Mice; D009474:Neurons / Q000166:cytology*; D016376:Oligonucleotides, Antisense / Q000494:pharmacology; D016548:Prosencephalon / Q000166:cytology* / Q000196:embryology*; D011509:Proteoglycans / Q000502:physiology; D018121:Receptors, Cytokine / Q000502:physiology; D053606:Receptors, OSM-LIF; D017465:Receptors, Opioid, delta / Q000037:antagonists & inhibitors; D013234:Stem Cells / Q000502:physiology*; D016212:Transforming Growth Factor beta
C525719:Bmp2 protein, mouse; C525810:Bmp4 protein, mouse; D055396:Bone Morphogenetic Protein 2; D055415:Bone Morphogenetic Protein 4; D019485:Bone Morphogenetic Proteins; D005904:Glial Fibrillary Acidic Protein; D006131:Growth Inhibitors; D015850:Interleukin-6; D053605:Leukemia Inhibitory Factor; D053680:Leukemia Inhibitory Factor Receptor alpha Subunit; C507838:Lif protein, mouse; C507841:Lifr protein, mouse; D008222:Lymphokines; D016376:Oligonucleotides, Antisense; D011509:Proteoglycans; D018121:Receptors, Cytokine; D053606:Receptors, OSM-LIF; D017465:Receptors, Opioid, delta; D016212:Transforming Growth Factor beta; D005346:Fibroblast Growth Factors; D007371:Interferon-gamma