Natural Science Forum / Biology / Biology / March 2008

this study suggests that controling cell proliferation is insufficient
to prevent differentiation and exit in time. nutrient supply can't be
a factor but perhaps certain growth factors remain elusive?

http://www.neuraldevelopment.com/content/3/1/4

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.

Conclusions
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.