Research article

Forcing neural progenitor cells to cycle is insufficient to alter cell-fate decision and timing of neuronal differentiation in the spinal cord

Valérie Lobjois^1,2* , Sophie Bel-Vialar^1* , Françoise Trousse^1,3 and Fabienne Pituello¹

¹  Centre de Biologie du Développement, UMR5547, Institut d'Exploration Fonctionnelle des Génomes IFR109, Université Toulouse III et Centre National de la Recherche Scientifique, 31062 Toulouse, France

²  Laboratoire de Biologie Cellulaire et Moléculaire du Contrôle de la Prolifération, UMR5088, Institut d'Exploration Fonctionnelle des Génomes IFR109, Université Toulouse III et Centre National de la Recherche Scientifique, 31062 Toulouse, France

³  Univ Montpellier 2, Montpellier, 34095 France; Inserm, U710, Montpellier, 34095 France; EPHE, Paris, 75007 France

author email corresponding author email* Contributed equally

Neural Development 2008, 3:4doi:10.1186/1749-8104-3-4

Published:	13 February 2008

Abstract

Background

During the development of the nervous system, neural progenitor cells can either stay in the pool of proliferating undifferentiated cells or exit the cell cycle and differentiate. Two main factors will determine the fate of a neural progenitor cell: its position within the neuroepithelium and the time at which the cell initiates differentiation. In this paper we investigated the importance of the timing of cell cycle exit on cell-fate decision by forcing neural progenitors to cycle and studying the consequences on specification and differentiation programs.

Results

As a model, we chose the spinal progenitors of motor neurons (pMNs), which switch cell-fate from motor neurons to oligodendrocytes with time. To keep pMNs in the cell cycle, we forced the expression of G1-phase regulators, the D-type cyclins. We observed that keeping neural progenitor cells cycling is not sufficient to retain them in the progenitor domain (ventricular zone); transgenic cells instead migrate to the differentiating field (mantle zone) regardless of cell cycle exit. Cycling cells located in the mantle zone do not retain markers of neural progenitor cells such as Sox2 or Olig2 but upregulate transcription factors involved in motor neuron specification, including MNR2 and Islet1/2. These cycling cells also progress through neuronal differentiation to axonal extension. We also observed mitotic cells displaying all the features of differentiating motor neurons, including axonal projection via the ventral root. However, the rapid decrease observed in the proliferation rate of the transgenic motor neuron population suggests that they undergo only a limited number of divisions. Finally, quantification of the incidence of the phenotype in young and more mature neuroepithelium has allowed us to propose that once the transcriptional program assigning neural progenitor cells to a subtype of neurons is set up, transgenic cells progress in their program of differentiation regardless of cell cycle exit.

Conclusion

Our findings indicate that maintaining neural progenitor cells in proliferation is insufficient to prevent differentiation or alter cell-fate choice. Furthermore, our results indicate that the programs of neuronal specification and differentiation are controlled independently of cell cycle exit.