Note to users. If you're seeing this message, it means that your browser cannot find this page's style/presentation instructions -- or possibly that you are using a browser that does not support current Web standards. Find out more about why this message is appearing, and what you can do to make your experience of our site the best it can be.
Subscribe

Logo for

J. Cell Sci. 116 (24): 4947-4955

Research Article

An inhibition of cyclin-dependent kinases that lengthens, but does not arrest, neuroepithelial cell cycle induces premature neurogenesis

Federico Calegari, and Wieland B. Huttner*

Max Planck Institute of Molecular Cell Biology and Genetics, Pfotenhauerstrasse 108, D-01307, Dresden, Germany

* Author for correspondence (e-mail: huttner{at}mpi-cbg.de)

Accepted for publication 6 August 2003.

Abstract: The G1 phase of the cell cycle of neuroepithelial cells, the progenitors of all neurons of the mammalian central nervous system, has been known to lengthen concomitantly with the onset and progression of neurogenesis. We have investigated whether lengthening of the G1 phase of the neuroepithelial cell cycle is a cause, rather than a consequence, of neurogenesis. As an experimental system, we used whole mouse embryo culture, which was found to exactly reproduce the temporal and spatial gradients of the onset of neurogenesis occurring in utero. Olomoucine, a cell-permeable, highly specific inhibitor of cyclin-dependent kinases and G1 progression, was found to significantly lengthen, but not arrest, the cell cycle of neuroepithelial cells when used at 80 µM. This olomoucine treatment induced, in the telencephalic neuroepithelium of embryonic day 9.5 to 10.5 mouse embryos developing in whole embryo culture to embryonic day 10.5, (i) the premature up-regulation of TIS21, a marker identifying neuroepithelial cells that have switched from proliferative to neuron-generating divisions, and (ii) the premature generation of neurons. Our data indicate that lengthening G1 can alone be sufficient to induce neuroepithelial cell differentiation. We propose a model that links the effects of cell fate determinants and asymmetric cell division to the length of the cell cycle.

Key Words: Neurogenesis • Olomoucine • TIS21 • Whole embryo culture

THIS ARTICLE HAS BEEN CITED BY OTHER ARTICLES:
Cell cycle and lineage progression of neural progenitors in the ventricular-subventricular zones of adult mice.
G. Ponti, K. Obernier, C. Guinto, L. Jose, L. Bonfanti, and A. Alvarez-Buylla (2013)
PNAS 110, E1045-E1054
   Abstract »    Full Text »    PDF »
Replication Protein A Links Cell Cycle Progression and the Onset of Neurogenesis in Drosophila Optic Lobe Development.
L. Zhou and H. Luo (2013)
J. Neurosci. 33, 2873-2888
   Abstract »    Full Text »    PDF »
Predicting stem cell fate changes by differential cell cycle progression patterns.
M. Roccio, D. Schmitter, M. Knobloch, Y. Okawa, D. Sage, and M. P. Lutolf (2013)
Development 140, 459-470
   Abstract »    Full Text »    PDF »
ATP-Binding Cassette G-Subfamily Transporter 2 Regulates Cell Cycle Progression and Asymmetric Division in Mouse Cardiac Side Population Progenitor Cells.
K.-I. Sereti, A. Oikonomopoulos, K. Unno, X. Cao, Y. Qiu, and R. Liao (2013)
Circ. Res. 112, 27-34
   Abstract »    Full Text »    PDF »
Disrupted ERK Signaling during Cortical Development Leads to Abnormal Progenitor Proliferation, Neuronal and Network Excitability and Behavior, Modeling Human Neuro-Cardio-Facial-Cutaneous and Related Syndromes.
J. Pucilowska, P. A. Puzerey, J. C. Karlo, R. F. Galan, and G. E. Landreth (2012)
J. Neurosci. 32, 8663-8677
   Abstract »    Full Text »    PDF »
GSK3 Temporally Regulates Neurogenin 2 Proneural Activity in the Neocortex.
S. Li, P. Mattar, D. Zinyk, K. Singh, C.-P. Chaturvedi, C. Kovach, R. Dixit, D. M. Kurrasch, Y.-C. Ma, J. A. Chan, et al. (2012)
J. Neurosci. 32, 7791-7805
   Abstract »    Full Text »    PDF »
Intermediate progenitors are increased by lengthening of the cell cycle through calcium signaling and p53 expression in human neural progenitors.
E. Garcia-Garcia, M. J. Pino-Barrio, L. Lopez-Medina, and A. Martinez-Serrano (2012)
Mol. Biol. Cell 23, 1167-1180
   Abstract »    Full Text »    PDF »
Apical migration of nuclei during G2 is a prerequisite for all nuclear motion in zebrafish neuroepithelia.
L. Leung, A. V. Klopper, S. W. Grill, W. A. Harris, and C. Norden (2011)
Development 138, 5003-5013
   Abstract »    Full Text »    PDF »
Cyclin D1 promotes neurogenesis in the developing spinal cord in a cell cycle-independent manner.
A. I. Lukaszewicz and D. J. Anderson (2011)
PNAS 108, 11632-11637
   Abstract »    Full Text »    PDF »
Physiological Relevance of Cell Cycle Kinases.
M. Malumbres (2011)
Physiol Rev 91, 973-1007
   Abstract »    Full Text »    PDF »
Adaptive Evolution of Four Microcephaly Genes and the Evolution of Brain Size in Anthropoid Primates.
S. H. Montgomery, I. Capellini, C. Venditti, R. A. Barton, and N. I. Mundy (2011)
Mol. Biol. Evol. 28, 625-638
   Abstract »    Full Text »    PDF »
Control of Activating Transcription Factor 4 (ATF4) Persistence by Multisite Phosphorylation Impacts Cell Cycle Progression and Neurogenesis.
C. L. Frank, X. Ge, Z. Xie, Y. Zhou, and L.-H. Tsai (2010)
J. Biol. Chem. 285, 33324-33337
   Abstract »    Full Text »    PDF »
Influence of Fat-Hippo and Notch signaling on the proliferation and differentiation of Drosophila optic neuroepithelia.
B. V. V. G. Reddy, C. Rauskolb, and K. D. Irvine (2010)
Development 137, 2397-2408
   Abstract »    Full Text »    PDF »
Forced G1-phase reduction alters mode of division, neuron number, and laminar phenotype in the cerebral cortex.
L.-J. Pilaz, D. Patti, G. Marcy, E. Ollier, S. Pfister, R. J. Douglas, M. Betizeau, E. Gautier, V. Cortay, N. Doerflinger, et al. (2009)
PNAS 106, 21924-21929
   Abstract »    Full Text »    PDF »
Cyclin D2 Is Critical for Intermediate Progenitor Cell Proliferation in the Embryonic Cortex.
S. B. Glickstein, J. A. Monaghan, H. B. Koeller, T. K. Jones, and M. E. Ross (2009)
J. Neurosci. 29, 9614-9624
   Abstract »    Full Text »    PDF »
Nonselective Sister Chromatid Segregation in Mouse Embryonic Neocortical Precursor Cells.
J.-F. Fei and W. B. Huttner (2009)
Cereb Cortex 19, i49-i54
   Abstract »    Full Text »    PDF »
Gsk3{beta}/PKA and Gli1 regulate the maintenance of neural progenitors at the midbrain-hindbrain boundary in concert with E(Spl) factor activity.
J. Ninkovic, C. Stigloher, C. Lillesaar, and L. Bally-Cuif (2008)
Development 135, 3137-3148
   Abstract »    Full Text »    PDF »
Neural stem cells: balancing self-renewal with differentiation.
C. Q. Doe (2008)
Development 135, 1575-1587
   Abstract »    Full Text »    PDF »
Six3 Controls the Neural Progenitor Status in the Murine CNS.
I. Appolloni, F. Calzolari, G. Corte, R. Perris, and P. Malatesta (2008)
Cereb Cortex 18, 553-562
   Abstract »    Full Text »    PDF »
BM88/CEND1 coordinates cell cycle exit and differentiation of neuronal precursors.
P. K. Politis, G. Makri, D. Thomaidou, M. Geissen, H. Rohrer, and R. Matsas (2007)
PNAS 104, 17861-17866
   Abstract »    Full Text »    PDF »
Interkinetic Nuclear Migration and the Selection of Neurogenic Cell Divisions during Vertebrate Retinogenesis.
L. M. Baye and B. A. Link (2007)
J. Neurosci. 27, 10143-10152
   Abstract »    Full Text »    PDF »
Mitotic spindle orientation distinguishes stem cell and terminal modes of neuron production in the early spinal cord.
A. C. Wilcock, J. R. Swedlow, and K. G. Storey (2007)
Development 134, 1943-1954
   Abstract »    Full Text »    PDF »
Cell Cycle-Specific and Cell Type-Specific Expression of Rb in the Developing Human Retina.
T. C. Lee, D. Almeida, N. Claros, D. H. Abramson, and D. Cobrinik (2006)
Invest. Ophthalmol. Vis. Sci. 47, 5590-5598
   Abstract »    Full Text »    PDF »
Overexpression of p27Kip1, Probability of Cell Cycle Exit, and Laminar Destination of Neocortical Neurons.
T. Tarui, T. Takahashi, R.S. Nowakowski, N.L. Hayes, P.G. Bhide, and V.S. Caviness (2005)
Cereb Cortex 15, 1343-1355
   Abstract »    Full Text »    PDF »
Selective Lengthening of the Cell Cycle in the Neurogenic Subpopulation of Neural Progenitor Cells during Mouse Brain Development.
F. Calegari, W. Haubensak, C. Haffner, and W. B. Huttner (2005)
J. Neurosci. 25, 6533-6538
   Abstract »    Full Text »    PDF »
Molecular dissection of Pax6 function: the specific roles of the paired domain and homeodomain in brain development.
N. Haubst, J. Berger, V. Radjendirane, J. Graw, J. Favor, G. F. Saunders, A. Stoykova, and M. Gotz (2004)
Development 131, 6131-6140
   Abstract »    Full Text »    PDF »

To Advertise     Find Products

Science Signaling. ISSN 1937-9145 (online), 1945-0877 (print). Pre-2008: Science's STKE. ISSN 1525-8882