The roles and mechanism of ultradian oscillatory expression of the mouse Hes genes

Abstract

Somites, metameric structures, give rise to the vertebral column, ribs, skeletal muscles and subcutaneous tissues. In mouse embryos, a pair of somites is formed every 2h by segmentation of the anterior parts of the presomitic mesoderm. This periodic event is regulated by a biological clock called the segmentation clock, which involves cyclic expression of the basic helix-loop-helix gene Hes7. Hes7 oscillation is regulated by negative feedback with a delayed timing. This process has been mathematically simulated by differential-delay equations, which predict that negative feedback with shorter delays would abolish oscillations or produce dampened but more rapid oscillations. We found that reducing the number of introns within the Hes7 gene shortens the delay and abolishes Hes7 oscillation or results in a more rapid tempo of Hes7 oscillation, increasing the number of somites and vertebrae in the cervical and upper thoracic region. We also found that Hes1, a Hes7-related gene, is expressed in an oscillatory manner by many cell types, including fibroblasts and neural stem cells. In these cells, Hes1 expression oscillates with a period of about 2-3h, and this oscillation is important for cell cycle progression. Furthermore, in neural stem cells, Hes1 oscillation drives cyclic expression of the proneural genes Ascl1 and Neurogenin2 and regulates multipotency. Hes1 expression oscillates more slowly in embryonic stem cells, and Hes1 oscillation regulates their fate preferences. Taken together, these results suggest that oscillatory expression with short periods (ultradian oscillation) is important for many biological events.

Keywords: Embryonic stem cell; Negative feedback; Neural stem cell; Oscillatory expression; Segmentation clock.