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The Journal of Neuroscience, August 1, 2002, 22(15):6610-6622
Contrasting Effects of Basic Fibroblast Growth Factor and
Neurotrophin 3 on Cell Cycle Kinetics of Mouse Cortical Stem Cells
Agnès
Lukaszewicz1,
Pierre
Savatier2,
Véronique
Cortay1,
Henry
Kennedy1, and
Colette
Dehay1
1 Institut National de la Santé et de la
Recherche Médicale U371, Cerveau et Vision, 69675 Bron, France,
and 2 Laboratoire de Biologie Moléculaire et
Cellulaire, Unité Mixte de Recherche 5665, Ecole Normale
Supérieure de Lyon, 69364 Lyon, France
Basic fibroblast growth factor (bFGF) exerts a mitogenic effect on
cortical neuroblasts, whereas neurotrophin 3 (NT3) promotes differentiation in these cells. Here we provide evidence that both the
mitogenic effect of bFGF and the differentiation-promoting effect of
NT3 are linked with modifications of cell cycle kinetics in mouse
cortical precursor cells. We adapted an in vitro assay, which makes it possible to evaluate (1) the speed of progression of the
cortical precursors through the cell cycle, (2) the duration of
individual phases of the cell cycle, (3) the proportion of proliferative versus differentiative divisions, and (4) the influence on neuroglial differentiation. Contrary to what has been claimed previously, bFGF promotes proliferation via a change in cell cycle kinetics by simultaneously decreasing G1 duration and
increasing the proportion of proliferative divisions. In contrast, NT3
lengthens G1 and promotes differentiative divisions. We
investigated the molecular foundations of these effects and show that
bFGF downregulates p27kip1 and upregulates cyclin D2
expression. This contrasts with NT3, which upregulates
p27kip1 and downregulates cyclin D2 expression.
Neither bFGF nor NT3 influences the proportion of glia or neurons in
short to medium term cultures. The data point to links between the
length of the G1 phase and the type of division of cortical
precursors: differentiative divisions are correlated with long
G1 durations, whereas proliferative divisions correlate
with short G1 durations. The present results suggest that
concerted mechanisms control the progressive increase in the cell cycle
duration and proportion of differentiative divisions that is observed
as corticogenesis proceeds.
Key words:
G1 phase; cell cycle; proliferation; neuroblast; time-lapse videomicroscopy; bFGF; NT3; corticogenesis
Copyright © 2002 Society for Neuroscience 0270-6474/02/22156610-13$05.00/0
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