Retinal stem cells in vertebrates
Muriel Perron and William A. Harris*
Summary
In fish and amphibia, retinal stem cells located in the
periphery of the retina, the ciliary marginal zone (CMZ),
produce new neurons in the retina throughout life. In
these species, the retina grows to keep pace with the
enlarging body. When birds or mammals reach adult
proportions, however, their retinas stop growing so
there appears to be no need for such a proliferative area
with stem cells. It is a surprise, therefore, that recent
data suggest that a region similar to the CMZ of fish and
amphibia exists in the postnatal chick and the adult
mouse.
(1±3)
BioEssays 22:685±688, 2000.
ß 2000 John Wiley & Sons, Inc.
Neural stem cells
Through asymmetric cell divisions, pluripotent neural stem
cells give rise to neurons on the one hand and of copies of
themselves on the other. Neural stem cells are found in all
vertebrates throughout embryogenesis, but as more and
more neurons differentiate, the populations of neural stem
cells dwindle, until in the adult only a few stem cells are left in
particular locations. Without the possibility of stem cell
replacement, the post-natal loss of neurons in most CNS
locations is irreversible, which is why degenerative neurolo-
gical diseases are so devastating. Until recently, neural stem
cells have only been found in a few places in adult mammals:
the olfactory epithelium, where sensory neurons are con-
stantly being replaced, and in the subventricular zone of the
forebrain whence new neurons are added to the olfactory
bulb and the hippocampus.
(4,5)
In adult song birds, such as
canaries, new neurons that arise from local ventricular stem
cells are added to singing centres in the brain each year
replacing the previous year's song circuitry.
(6,7)
But not all
CNS areas in the adult CNS have local stem cells, and even
in lower vertebrates there are only a few specialised zones,
such as the CMZ (also called the ora serrata)of the retina,
where the stem cells are maintained.
The CMZ: a stem cell-containing region at the
peripheral region of the retina
The vertebrate retina contains a limited number of neuronal
cell types organised in layers and surrounded by a retinal
pigmented epithelium (RPE). In fish and amphibia, the
continuous growth of the retina is due to the addition of
concentric rings of new retinal cells from the most peripheral
region of the retina, the CMZ.
(8±13)
A pulse of bromodeox-
yuridine (BrdU), therefore, labels cells in the CMZ of these
adult animals.
(14)
Using molecular markers, such as proneur-
al and neurogenic genes, it has been shown that the spatial
distribution of cells in the CMZ, from peripheral to central,
reflects the temporal development of the retina (Fig. 1).
(15)
In
Xenopus, the CMZ can be subdivided into at least four
zones, each one giving rise to the next. The youngest and
least determined of the dividing cells are the closest to the
periphery these are self-renewing retinal stem cells. This
zone generates the more central pluripotent retinoblasts,
destined to produce large but limited clones of cells of all
retinal types. Arising from these are the more central
retinoblasts with more restricted fates and more limited
proliferative propensity. The daughters of these retinoblasts
are cells at the central edge of the CMZ that have stopped
dividing and begun to differentiate.
(10,15,16)
Thus it seems
that retinal stem cells and their progeny in the most
peripheral part of the adult CMZ in lower vertebrates faithfully
and continuously recapitulate the embryonic generation of
the retina throughout life.
In birds and mammals, although the whole eye continues
to grow for a time postnatally, most evidence suggests that
this growth is not from the addition of new cells but, rather,
from stretching of the retina associated with the growth of the
orbit. This leads to increased cellular spacing in the retina.
(17)
Using BrdU labelling, Fisher and Reh now provide evidence
of a proliferating marginal zone in postnatal chicks.
(1)
They
show that addition of new retinal cells from the peripheral
edge occurs for at least three weeks after hatching. Using
double labelling for BrdU and markers for post-mitotic
neurons, the authors show that these dividing cells in the
marginal zone of the chick retina give rise to cells that are
integrated into the retina. As in frogs and fish, the BrdU-
positive cells are found primarily in the inner nuclear layer,
which contains amacrine, bipolar, or Mu
È
ller cells. However,
these progenitors tend not to produce ganglion, horizontal or
photoreceptor cells. The multipotentiality seen in amphibia
CMZ stem cells seems therefore, restricted in the chick.
BioEssays 22:685±688, ß 2000 John Wiley & Sons, Inc. BioEssays 22.8 685
Department of Anatomy, University of Cambridge, UK.
Present address of Muriel Perron: Laboratoire d'Embryologie
Mole
Â
culaire, Universite
Â
Paris-Sud.
Funding agencies: The European Commission and the Wellcome
Trust to W.A.H. A European TMR Marie-Curie fellowship and the
CNRS supported M.P.
*Correspondence to: Professor William A. Harris, Department of
Anatomy, University of Cambridge, CB2 3DY, UK.
E-mail: harris@mole.bio.cam.ac.uk
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