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 model of Down syndrome (DS), is characterized by a transient delay in the radial expansion of the cortical wall and a persistent reduction in cortical volume. 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 in Ts16 than in euploid progenitors, the Ts16 growth fraction was reduced, and an increase in apoptosis was observed in both proliferative and postmitotic zones of the developing Ts16 neocortical wall. Incorporation of these changes into a model of neuronogenesis indicates that they are sufficient to account for the observed delay in radial expansion. In addition, the number of neocortical founder cells, i.e., precursors present just before neuronogenesis begins, is reduced by 26% in Ts16 mice, leading to a reduction in overall cortical size at the end of Ts16 neuronogenesis. Thus, altered proliferative characteristics during Ts16 neuronogenesis result in a delay in the generation of neocortical neurons, whereas the founder cell deficit leads to a proportional reduction in the overall number of neurons. Such prenatal perturbations in either the timing of neuron generation or the final number of neurons produced may lead to significant neocortical abnormalities such as those found in DS.
Haydar
T F
TF
Department of Physiology, University of Maryland School of Medicine, Baltimore, Maryland 21201, USA.
Nowakowski
R S
RS
Yarowsky
P J
PJ
Krueger
B K
BK
D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D002452:Cell Count; D002453:Cell Cycle / Q000502:physiology; D002455:Cell Division / Q000502:physiology; D002467:Cell Nucleus / Q000473:pathology; D002470:Cell Survival / Q000502:physiology; D002540:Cerebral Cortex / Q000473:pathology; D005260:Female; D018703:Founder Effect; D007150:Immunohistochemistry; D007621:Karyotyping; D051379:Mice; D008810:Mice, Inbred C57BL; D008831:Microcephaly / Q000196:embryology* / Q000235:genetics / Q000473:pathology*; D019579:Neocortex / Q000166:cytology / Q000502:physiology; D009474:Neurons / Q000502:physiology*; D014314:Trisomy / Q000235:genetics / Q000473:pathology*