Role of founder cell deficit and delayed neuronogenesis in microencephaly of the trisomy 16 mouse

Development of the neocortex of the trisomy 16 (Ts16) mouse, an animal mode l of Down syndrome (DS), is characterized by a transient delay in the radia l expansion of the cortical wall and a persistent reduction in cortical vol ume. Here we show that at each cell cycle during neuronogenesis, a smaller proportion of Ts16 progenitors exit the cell cycle than do control, euploid progenitors. In addition, the cell cycle duration was found to be longer i n Ts16 than in euploid progenitors, the Ts16 growth fraction was reduced, a nd an increase in apoptosis was observed in both proliferative and postmito tic zones of the developing Ts16 neocortical wall. Incorporation of these c hanges into a model of neuronogenesis indicates that they are sufficient to account for the observed delay in radial expansion. In addition, the numbe r of neocortical founder cells, i.e., precursors present just before neuron ogenesis begins, is reduced by 26% in Ts16 mice, leading to a reduction in overall cortical size at the end of Ts16 neuronogenesis. Thus, altered prol iferative characteristics during Ts16 neuronogenesis result in a delay in t he generation of neocortical neurons, whereas the founder cell deficit lead s to a proportional reduction in the overall number of neurons. Such prenat al perturbations in either the timing of neuron generation or the final num ber of neurons produced may lead to significant neocortical abnormalities s uch as those found in DS.