論文

Neural Hu proteins (HuB/C/D) are RNA-binding proteins that have been shown to induce neuronal differentiation activity when overexpressed in immature neural progenitor cells or undifferentiated neuronal tumors. Newly generated HuD-deficient mice exhibited a transient impaired-cranial-nerve-development phenotype at an early embryonic stage. Adult HuD-deficient mice exhibited an abnormal hind-limb reflex and poor rotarod performance. Analysis of neurosphere formation revealed that the number and self-renewal capacity of the neural stem/progenitor cells were increased in HuD-deficient mice. HuD-deficient primary neurospheres also generated a smaller number of neurons. Cohort analysis of the cellular proliferative activity by using BrdUrd and iododeoxuridine labeling revealed that the number of differentiating quiescent cells in the embryonic cerebral wall was decreased. Long-term administration of BrdUrd revealed that the number of slowly dividing stem cells in the adult subventricular zone was increased in the HuD-deficient mice. Taken together, the results suggest that HuD is required at multiple points during neuronal development, including negative regulation of proliferative activity and neuronal cell-fate acquisition of neural stem/progenitor cells.

The number and distribution of neurons in the murine neocortex are altered by loss of function of p27Kip1, a cyclin-dependent kinase inhibitor that regulates cell cycle progression at the G1 phase. We show that a temporary decline in the production of non-GABAergic projection neurons occurs in the dorsomedial neopallium of the p27Kip1 knockout mouse during the mid-term of neuronogenesis. It is followed by an augmentation of neuron production later in neuronogenesis leading to an increased production of projection neurons for the upper layers of the neocortex (layers II-IV). p27Kip1 is likely to play a critical role in cell internal regulatory mechanisms of proliferation/differentiation behavior of neural progenitor cells and may be directly involved in the control of neuron number during the period when non-GABAergic projection neurons for layers II-IV are being produced.