Misc

Recent advancements in the research field of stem cell biology have enabled the realization of regenerative medicine in various systems of the body, including the central nervous system. However, fundamental knowledge regarding how neural stem cells divide and generate young neurons in mammals, especially in vivo, is still inadequate. In this article, we shall summarize the concept of cell cycle/division of neural stem cells that generate projection neurons in the murine cerebral cortex. We shall also review the molecular mechanisms that modulate the critical parameters related to the cell cycle regulatory mechanisms, with special reference to the cell cycle regulatory protein p27Kip1 , an inhibitor of progression of the cell cycle at the G1 phase. A better understanding of the mechanisms controlling cell cycle progression is expected to contribute to the development of novel strategies to increase the efficiency of neural cell/tissue production, both in vivo and in vitro.

Brain size variation among different mammals is tightly associated with different levels of cerebral function. Mechanisms that regulate the number of neurons and hence the size of the brain must be at least partially embedded within the very early phase of neocortical development, that is, embedded in proliferation/differentiation characteristics of the neural progenitor cells (NPCs) of the neocortex. Here we review a sequence of critical events through which the neocortex is formed in the embryonic forebrain, with particular emphasis on cell cycle kinetics of the NPCs that produce non-GABAergic projection neurons, the majority of neurons in the neocortex. In general, the critical parameters that determine the total number of cells produced by a given progenitor population through a sequence of cell cycles are (1) the number of cell cycles that constitute the production period and (2) the probability of cell cycle exit (Q fraction or Q) of progenitor cells for each of the cell cycles. We will also review molecular mechanisms that modulate the critical parameters above, with a special reference to the cell cycle regulatory protein p27(Kip1), inhibitor of G1 phase progression of the cell cycle. Finally the neocortical dysgenesis caused by genetic modification in mice where p27(Kip1) is either deleted or overexpressed is presented as examples of neuron number changes and resultant neocortical dysgenesis by Q fraction alteration.