In neural progenitor cells (NPCs), Hes1 expression oscillates through a self-inhibitory, negative-feedback loop. It is known that the sustained (non-oscillatory) expression of Hes1 inhibits NPC proliferation, although it is unclear whether the constant expression of Hes1, or the higher level of Hes1 protein that results from sustained expression, is responsible for this phenotype. Here, Ryoichiro Kageyama and colleagues address this problem by engineering mice with shorter (type-1) and longer (type-2) Hes1 expression cycles through the decrease or increase of transcriptional delays, respectively. Although Hes1 type-2 animals are morphologically normal, Hes1 type-1 mice develop smaller brains, caused by decreased NPC proliferation and increased levels of apoptosis. In Hes1 type-1 mice, which have three introns removed, the periodicity of Hes1 cycles is about 14 minutes shorter and Hes1 expression is about 70% of that in wild-type animals. Importantly, the expression of Hes1 in type-1 mice is comparable to Hes1+/− mice, which do not have brain defects. Furthermore, additional loss of Hes3 and Hes5 in Hes1 type-1 mice accelerates neuronal differentiation. These data indicate that Hes1 oscillations, rather than the level of Hes1 expression, regulate the maintenance, proliferation and differentiation of NPCs, and the timing of neurogenesis.
