Background Through 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. 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 CCT137690 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. Background Embryonic neural stem cells can either proliferate thereby maintaining a pool of undifferentiated neural progenitor cells or differentiate into neurons or macroglial cells. In the developing nervous system two principal factors determine the fate of the differentiating neurons or glia: the position of the neural progenitor cell within the neuroepithelium and the timing of initiation of its differentiation. In the developing spinal cord the ventricular zone contains neural progenitor cells that are subdivided into groups destined for distinct neuronal differentiation . At early CCT137690 developmental phases the ventral neural progenitor cells termed progenitors of engine neurons (pMNs) can create engine neurons while at later on phases they differentiate into oligodendrocytes. The pMNs communicate a unique mix of homeodomain transcription elements resulting in the upregulation of the essential helix-loop-helix (bHLH) transcription element Olig2 [2-6]. Olig2 occupies an integral nodal stage in the pathway adding to the rules of both homeodomain transcription factors which determine motor neuron subtype specification and bHLH factors like the proneural factor neurogenin 2 (Ngn2) which drive neurogenesis. Oligodendrocyte production requires the ongoing activity of Olig2 and is preceded by downregulation of Ngn2 a determinant of the neuron-glial switch . While oligodendrocytes retain the capacity to divide after leaving the neural progenitor domain neuronal progenitor cells exit the cell cycle prior to initiating migration and differentiation in the mantle layer. Cell cycle exit represents part of the proneural activity of Ngn2 [3 4 8 The impact of the timing of cell cycle exit on neural cell fate and the timing of neuronal Rabbit polyclonal to AKAP5. differentiation remains unclear. Data indicate that cell cycle exit alone is insufficient to trigger neuronal differentiation [11 12 Conversely the onset of neuronal differentiation may be hindered by forcing neural progenitor cells to cycle CCT137690 . D-type cyclins (CyclinDs) are known to govern progression in G1 and forced expression of CyclinDs at early stages of spinal cord development keeps neural progenitor cells proliferating impeding neuronal differentiation . CCT137690 In the hindbrain of jumonji (jmj) mutant mice failure to turn off CyclinD1 alters the timing of neuronal differentiation. Although the cells migrate into the differentiating field they retain neural progenitor traits including the ability to divide. This phenotype is rescued by crossing the jmj mutant with CyclinD1 knockout mice . Reports also exist.