Oscillatory Control of Factors Determining Multipotency and Fate in Mouse Neural Progenitors
authors contributed equally to this work. Abstract: The basic-helix-loop-helix transcription factors Ascl1/Mash1, Hes1, and Olig2 regulate fate choice of neurons, astrocytes, and oligodendrocytes, respectively. These same factors are coexpressed by neural progenitor cells. Here, we found by time-lapse imaging that these factors are expressed in an oscillatory manner by mouse neural progenitor cells. In each differentiation lineage, one of the factors becomes dominant. We used optogenetics to
... trol expression of Ascl1, and found that although sustained Ascl1 expression promotes neuronal fate determination, oscillatory Ascl1 expression maintains proliferating neural progenitor cells. Thus, the multipotent state correlates with oscillatory expression of several fate-determination factors, whereas the differentiated state correlates with sustained expression of a single factor. Word limit includes text + references + figure and table legends inserted in frame into the 5' region of the Hes5 gene for Hes5 imaging (table S1, fig. S2B,C) , and Sox2 reporter mice expressing a Luc2-Sox2 fusion protein (table S1, fig. S1G ). The reporter expression in these mice was similar to endogenous expression ( fig. S3 ). Reporter expression also correlated well with endogenous protein expression in NPCs (fig. S4 ). The brain structures and the NPC competency of these reporter mice including homozygous Venus-Hes1 fusion knock-in mice were apparently normal ( fig. S5 ). We used time-lapse imaging of brain slices from the ventral telencephalon of reporter mice and found that Hes1 and Ascl1 expression oscillate in NPCs (Fig. 1I -K, movie S1).