Notch signaling, the segmentation clock, and the patterning of vertebrate somites

Abstract

The Notch signaling pathway has multifarious functions in the organization of the developing vertebrate embryo. One of its most fundamental roles is in the emergence of the regular pattern of somites that will give rise to the musculoskeletal structures of the trunk. The parts it plays in the early operation of the segmentation clock and the later definition and differentiation of the somites are beginning to be understood.

Figure 1

Basic principles of Delta-Notch signaling. Notch is a cell-surface receptor whose ligand Delta is also expressed on the cell surface. Binding of Delta to Notch activates cleavage of Notch at the membrane, thereby releasing the Notch intracellular domain (NICD), which migrates to the nucleus where it functions in transcriptional regulation. The detached extracellular fragment of Notch, NECD, along with Delta, is endocytosed into the Delta-expressing cell.

Figure 2

Lateral inhibition in differentiation. Two neighboring cells each express both the Notch receptor and its ligand, Delta, but the cell on the left expresses Delta more strongly, so that the Hes/her gene is activated in the neighboring cell (on the right), and its product, an inhibitory transcriptional regulator, acts in this cell to block expression both of Delta and of genes for differentiation. Consequently, in the left-hand cell Notch is not activated, the Hes/her gene is not transcribed, Delta expression is maintained, and genes specifying differentiation are expressed.

Figure 3

Somitogenesis and the segmentation clock. (a) The pattern of expression of one of the oscillatory genes – deltaC – during somitogenesis in the zebrafish. Two specimens are shown, fixed and stained by in situ hybridization (ISH) at different phases of their somitogenesis cycle. (b) Diagram showing how the observed pattern of gene expression reflects the cyclic behavior of the individual cells. Each cell contains a gene-expression oscillator – a clock – which slows down as the cell moves from the posterior to the anterior part of the PSM, giving rise to a pattern of stripes of cells in different phases of their oscillation. The oscillation is halted as cells emerge from the PSM, leaving them arrested in different states (blue versus white shading), thereby demarcating the somite boundaries (black lines). The extent of the PSM is defined by an Fgf + Wnt signal gradient, with its origin at the tail end of the embryo.

Figure 4

Disruption of somite patterning in a Notch mutant. When Notch signaling fails, the individual cells (in zebrafish at least) continue to oscillate but fall out of synchrony, and somite patterning breaks down.

Figure 5

Autoregulation of Hes/her genes. On activation, the her1/7 gene produces an inhibitory transcriptional regulator that acts to suppress transcription of the her1/7 gene itself, but only after a delay for transcription (T_m) and translation (T_p). This can give rise to oscillations,