HES1 - HES1 and Stem Cells - Neural Development

Neural Development

HES1 is expressed in both neuroepithelial cells and radial glial cells, both neural stem cells. Hes1 expression, along with that of Hes5, covers the majority of the developing embryo at embryonic day 10.5. After this point, expression of Hes1 is limited to the subventricular zone. In HES1 knockout (KO) mice, Mash1 is compensatorily upregulated, and neurogenesis is accelerated. Indeed, if the expression of Hes1, Hes3, and Hes5 genes is inhibited, the expression of proneural genes increases, and while neurogenesis is accelerated, neural stem cells become prematurely depleted. Contrariwise, if these HES genes are overexpressed, neurogenesis is inhibited. Thus HES1 genes are only involved in maintaining, not creating, neural stem cells.

Additionally, HES1 can guide neural stem cells down one of two paths of differentiation. HES1 can maintain neural stem cells expressing Pax6, but leads cells that are Pax6-negative to an astrocyte differentiation fate. Epigenetic modifications such as DNA methylation also influence HES1's ability to direct differentiation. Demethylation of HES1 target sites in the promoter region of astrocyte-specific genes hastens astrocyte differentiation. The oscillatory nature of Hes1 expression has a role in determining differentiation fate as well. HES1-high embryonic stem cells that received a differentiation signal often adopted a mesodermal fate, while HES1-low cells that received a differentiation signal differentiated into neuronal cells. These results were confirmed using q-PCR which showed that HES1-high cells showed high levels of Brachyury and Fgf5 expression (both of which are expressed highly in mesodermal cell types) with comparatively low levels genes expressed in neural cells such as Nestin. By contrast, HES1-low cells showed high levels of expression of genes involved in neural induction and low levels of expression of genes involved in mesodermal differentiation. Cycling HES1 levels also contribute to the maintenance of neural progenitor cells by regulating Neurogenin2 (Ngn2) and Dll1 oscillations. Interestingly, Hes1 levels fluctuate at different frequencies in different parts of the central nervous system: HES1 is continuously expressed at high levels in the boundaries, but vacillates in the compartments. This suggests that alternating HES1 levels may prompt differences in characteristics between anatomical elements of the central nervous system.