Fig. 5.

A, Schematic model of neurogenesis in wild-type (wild) and Hes1^−/−mice (Hes1^−/−) based on the present results in vivo and in vitro. Because theHes1 mutation relieves the repression of neuronal commitment by MPs, the self-renewing capability of MPs is lowered (Fig. 2, represented as the thin circular arrow beside theHes1^−/− MPs in Fig. 5A), and the generation of NPs is increased (Table 1, more NPs are generated from Hes1^−/− MPs in Fig.5A). Prematurely committed, abnormal NPs become apoptotic (*1) or prematurely stop undergoing mitosis (*2) (accelerated apoptosis and a decreased number of daughter neurons from each NP; Figs. 3, 4). The increased number of neurons in early neurogenesis (before the lethal point ofHes1^−/− mice around E14;transverse line in A) inHes1^−/− mice (Fig. 1) corresponds to the premature commitment and differentiation of cells in the neuronal lineage. Dotted lines encircle the representative lineage of single NPs based on the low-density culture experiments (Fig. 3). NPs of Hes1^−/− mice are likely to have ceased mitosis prematurely. There are two possible mechanisms to explain this premature cessation: (1) the accelerated transition of the developmental stages from NP to N, and from MP to NP, and (2) interruption of asymmetric cell division by the Hes1mutation. B, Diagrammatic representation of the regulation of neurogenesis by the Hes family. This diagram is based on the results of this and previous studies. Neurons (N) are derived from multipotent progenitor cells (MP); that is, a neural stem cell (MP), directly or via an intermediate progenitor state, becomes a committed neuronal progenitor cell (NP). Commitment and differentiation are two important, distinct steps in neurogenesis. Hes1 represses the commitment of MPs to the neuronal lineage, but not to glial lineages (*3; Table 1). Hes1 and Hes5 repress neuronal differentiation in a redundant manner (*4; Figs. 1,3; Ohtsuka et al., 1999).