Roles of cell cycle regulatory protein p27 in murine neocortical histogenesis

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p27^<kip1> is a cell cycle regulatory protein that inhibits G1 phase progression and induces cell differentiation. In p27^<kip1> knockout mouse (p27KO), the size of the brain is increased by about 30 %. We previously observed that both thickness and number of non-GABAergic neurons in the cortical layers II-IV were significantly increased in p27KO as compared to the WT littermates. These suggest that output from the NPCs in the middle to late period of neuronogenesis was increased by loss of function of p27^<kip1>. To investigate the histogenetic mechanisms of the cortical malformation in p27KO, we have studied proliferation and differentiation characteristics of the NPCs in the p27KO at embryonic day 14 (E14).The cell cycle length of the NPCs at E14 was indistinguishable between p27KO and WT. However, the number of the newly differentiated neurons (Q cells) at E14 was reduced in p27KO. The consequence is that there is proliferative augmentation of NPCs in the p27KO animals at E14. The distribution pattern of the Q cells in the p27KO was also abnormal. The exit behavior of Q cells from the proliferative epithelium is bimodal in both genotypes ; partitioned into rapidly and slowly exiting subpopulations. The reduction in the Q fraction in the p27KO is assignable entirely to the rapidly exiting subset of Q cells.The neocortical malformation in the p27KO is likely to be attributable to an abnormal pattern of the ascent of Q fraction during the middle phase of neuronogenetic interval.