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FIGURE 4.20 Clone of cells in the Xenopus retina. A. Daughters
of a single retinal progenitor injected with horseradish peroxidase
form a column that spans the retinal layers and contributes many
distinct cell types. B. p, photoreceptor; b, bipolar cell; m, Müller cell;
a, amacrine cell, g, ganglion cell.
FIGURE 4.21 Determination in a vertebrate retina. A. A progen-
itor cell in the neuroepithelium divides several times and gives rise
to clones of cells that contain all the major cell types of the retina,
including Ganglion cells G, Amacrine cells A, Horizontal cells H,
Bipolar cells B, Rods R, Cones C, and Müller cells M. These cells tend
to be born at different developmental times, indicating a rough his-
togenetic order that is shown in (B).
into RGCs in culture. Progenitors isolated at a later
stage tend to become rods (Watanabe and Raff, 1990)
(Figure 4.22). And while it is not impossible, it is cer-
tainly more difficult for older progenitors to assume
early fates than it is for early progenitors to assume late
fates. This is shown by heterochronic experiments. If
retinal cells that are born at the stage when RGCs are
normally being born are labeled and mixed together
into an aggregate and cultured in vitro , the labeled
cells still differentiate into RGCs and few become rods.
If, however, they are mixed with an excess of retinal
cells that are several days older, the same cells have a
higher probability of becoming rods (Watanabe and
Raff, 1990). The other direction is much harder; that is,
few late progenitors choose RGC fates, even when
mixed with an excess of cells from earlier retinas
(James et al., 2003).
The bHLH and homeobox transcription factors look
as though they are intrinsic factors that help specify
retinal cell fate. Among the homeobox factors, Chx10 is
involved in bipolar fate, Prox1 in horizontal cell fate,
and BarH1 in RGC fate. Among the bHLH genes, Ath5
is absolutely critical RGC fate. The example of Ath5 is
particularly interesting. Ath5 is turned on transiently in
retinal precursor development. In animals where Ath5
is never expressed, the RGCs simply do not arise. Yet
other retinal cells are formed in Ath5 knockouts. This
suggests that when this factor is downregulated, retinal
precursors are no longer competent to make RGCs.
Moreover, when retinal progenitors are forced out of
the cell cycle by the expression of cell-cycle inhibitors,
at a time when they express Xath5 , they have an
increased tendency to make RGCs, suggesting that
the retinal progenitors are like the neuroblasts of the
Drosophila CNS, which go through a succession of tran-
scription factors. The external factors that influence
competence may then turn out to be factors that influ-
ence cells to exit the cell cycle and differentiate rather
than factors that influence the expression of specific
homeobox or bHLH genes directly.
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