Figure 8. Schematic model of the regulation of Notch pathway genes and the segmentation clock by the Wnt3a/β-catenin target gene Msgn1.

The Wnt3a/β-catenin pathway directly activates Msgn1 and Dll1. Msgn1 binds directly to regulatory enhancers to activate gene expression in the PSM. Direct activation of Dll1 by Msgn1 establishes a feed-forward loop that ensures strong activation of Dll1 by Wnt signals. Msgn1 synergizes with activated Notch to activate Lfng. The Notch target, and clock pacemaker, Hes7, functions in an autoinhibitory feedback loop (blue lines) to periodically repress its own expression, and that of Lfng, thereby driving the oscillating segmentation clock. The ability of Msgn1 to bridge the Wnt and Notch pathways suggests an explanation for the antiphase nature of Wnt and Notch clock gene expression¹³. Active Wnt signaling initiates the expression of Msgn1 and cyclic Wnt target genes such as Axin2, while a phase-lag, to allow for the transcription and translation of Msgn1 and the activation of Msgn1-Notch target genes, leads to the delayed expression of Lfng. For simplicity, several target genes, gene products, and regulatory interactions are not shown. Abbr.: N, Notch intracellular domain.