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Although the intrinsic transcription factors like
Ath5 are critical for directing progenitors to specific
fates, as noted above, cellular interactions can control
the process to some extent. As we have already seen in
examples from Drosophila, Notch signaling is an
important mediator of cellular interactions that allow
cells to choose different fates. Notch signaling is also
very important in helping specify fate in the develop-
ing vertebrate retina. When Notch is overactive over
an extended period, cell differentiation is delayed, and
as a result, most retinal cells take late fates such as
Müller glia (see above). Alternatively, if Notch signal-
ing is blocked through the misexpression of dominant
negative mutant genes, most retinal cells take on early
fates such as RGCs. The idea proposed for Notch func-
tion in the vertebrate retina is that it allows only a
certain number of cells to differentiate at any one time.
This is critical when cells are making decisions based
on the cues they receive in a rapidly changing envi-
ronment. Thus, fates appear that are appropriate for
the time at which they differentiate (Dorsky et al., 1997;
Henrique et al., 1997). If all the cells were permitted to
differentiate at the same instant, they might do so in
more or less the same environment, and they might all
choose the same fate!
Findings such as the above provide strong insights
into the relationship between histogenesis and cell fate,
as cells that pull out of the cell cycle at times when they
express specific transcription factors may tend to
produce fates based on these factors. A variety of exter-
nal growth factors influence cell-cycle progression by
affecting the expression of cell-cycle components (see
Chapter 3). In the retina, as in many other parts of the
CNS, glia are the last cells to pull out of the cell cycle.
In the Xenopus retina, this is by virtue of an accumula-
tion of a cell-cycle inhibitor called p27Xic1. If a retinal
precursor expresses a proneural gene, like the atonal
homolog Ath5, it may leave the cell cycle and differen-
tiate as a neuron, but Notch activation in the precursor
antagonizes the expression of the proneural genes like
Ath5 and allows precursor to build up p27Xic1. Inter-
estingly, p27Xic1 is a bifunctional molecule. It has a
cyclin kinase inhibitor domain to take the cells out of
the cell cycle, and it has a separate Müller glial deter-
mination domain. The p27Xic1 forces the last dividing
retinoblasts, those that have not been determined to
become neurons, both to leave the cell cycle and to
become Müller cells (Ohnuma et al., 1999). Thus, the
neurogenic signaling pathway and the factors that
regulate the cycle in the vertebrate retina are basic
regulatory mechanisms that can be used to generate
neuronal diversity by affecting the timing of differenti-
ation in the changing external environment, linking
histogenesis with determination.
A
Embryonic day 14
Postnatal day 0
Label progenitors
with 3 H-thymidine
Retina
Dissociate
Dissociate
Rod
RGC
RGC
Rod
Many labeled cells
develop as RGCs
Many labeled cells
develop as rods
Isochronic
Heterochronic
B
Unlabeled
Labeled
Unlabeled
Labeled
E15 progenitor
P1 progenitor
Rod
RGC
RGC
Rod
500
0
Isochronic
(E15-E15)
Heterochronic
(E15-P1)
FIGURE 4.22 A. Birthdate and cell fate. Cells born on E14, even
if dissociated into tissue culture, tend to differentiate into Retinal
Ganglion Cells (RGCs), while cells born on P0, when dissociated,
tend to differentiate into Rods. B. Early cell fate in the vertebrate
retina is flexible and influenced by extrinsic factors. E15 cells labeled
with thymadine and mixed with other E15 cells (isochronic) will not
tend to differentiate as rods, while the same cells, if mixed with P0
cells (heterochronic) will. (After Watanabe and Raff, 1990)
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