The Questions of Developmental Biology

In the absence of Notch gene transcription in the embryo, these cells develop exclusively
into neuroblasts, rather than into a mixture of hypodermal and neural precursor cells (Artavanis-
Tsakonis et al. 1983; Lehmann et al. 1983). These embryos die, having a gross excess of neural
cells at the expense of the ventral and head hypodermis (Poulson 1937; Hoppe and Greenspan
1986).
Heitzler and Simpson (1991) have proposed that the Notch protein, like LIN-12, serves as
a receptor for intercellular signals involved in differentiating equivalent cells. Moreover, they
provided evidence that Delta is the ligand for Notch. Genetic mosaics show that whereas Notch is
needed in the cells that are to become hypodermis, Delta is needed in the cells that induce the
hypodermal phenotype.
Greenwald and Rubin (1992) have proposed a model based on the LIN-12 hypothesis to
explain the spacing of neuroblasts in these proneural clusters of epidermal and neural precursors
(Figure 6.31). Initially, all the cells have equal potentials and produce the same signals. However,
when one of the cells, by chance, produces more signal (say, Delta protein), it activates the
receptors on adjacent cells and reduces their signaling level. Since the signaling levels on
adjacent cells are lowered, the neighbors of those low-signaling cells will tend to become highlevel
signalers. In this way, a spacing of neuroblasts is produced.
Juxtacrine Signaling
In juxtacrine interactions, proteins from the inducing cell interact with receptor proteins
of adjacent responding cells. The inducer does not diffuse from the cell producing it. There are
three types of juxtacrine interactions. In the first type, a protein on one cell binds to its receptor
on the adjacent cell. We saw this type of juxtacrine interaction when we discussed the interaction
between the Bride of sevenless protein and its receptor, Sevenless. In the second type, a receptor
on one cell binds to its ligand on the extracellular matrix secreted by another cell. In the third
type, the signal is transmitted directly from the cytoplasm of one cell through small conduits into
the cytoplasm of an adjacent cell.
The Notch pathway: Juxtaposed ligands and receptors
While most known regulators of induction are diffusible proteins, some inducing proteins
remain bound to the inducing cell surface. In one such pathway, cells expressing the Delta,
Jagged, or Serrate proteins in their cell membranes activate neighboring cells that contain the
Notch protein in their cell membranes. Notch extends through the cell membrane, and its external
surface contacts Delta, Jagged, or Serrate proteins extending out from an adjacent cell. When
complexed to one of these ligands, Notch undergoes a conformational change that enables it to be
cut by a protease. The cleaved portion enters the nucleus and binds to a dormant transcription
factor of the CSL family. When bound to the Notch protein, the CSL transcription factors activate
their target genes (Figure 6.29A; Lecourtois and Schweisguth 1998; Schroeder et al. 1998; Struhl
and Adachi 1998 ).