XB-ART-14602Semin Cell Dev Biol June 1, 1998; 9 (3): 241-7.
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Inductive competence, its significance in retinal cell fate determination and a role for Delta-Notch signaling.
The retina is a favorite model for studying determination and differentiation in the central nervous system because of its ready accessibility, diversity of cell types and regular organization. Many molecules which act as potential inducers of cell fate have been identified by exposing progenitors to them and assaying their differentiation. In addition, heterochronic transplants demonstrate that regulation of cellular competence (i.e. the ability of progenitors to respond to inducers) plays an important role in differentiation. The neurogenic genes Delta and Notch acting as ligand and receptor, respectively, play a role in regulating cell competence by normally inhibiting progenitors from differentiating. Misexpression of an activated form of Notch ''freezes'' progenitors in an undifferentiated, neuroepithelial state. Conversely, progenitors failing to be inhibited, either by their own overexpression of Delta, or by a dominant-negative Delta construct which blocks signaling, adopt the earliest fates generated in the retina (i.e. cones and ganglion cells). We suggest that retinal progenitors use lateral inhibition mediated by Delta-Notch to regulate their competence to respond to inductive cues in a changing environment. Such signaling is essential for formation of the proper cell types in appropriate numbers at the right stage of development to make functional circuits.
PubMed ID: 9665858
Article link: Semin Cell Dev Biol
Species referenced: Xenopus laevis
Genes referenced: hspa5 notch1
Antibodies: Hspa5 Ab1
Article Images: [+] show captions
|Figure 1. The experimental paradigm for in vivo heterochronic transplant and an example of data obtained. At the top fertilized eggs being injected with fluorescein-dextran (one blastomere injected, one being injected) are shown. These embryos were grown at 17°C and a quadrant of the optic vesicle was removed. Two cohorts of uninjected embryos were kept to serve as hosts for the transplant, one was raised at 17°C and therefore developed at the same rate, the other was raised at 22°C causing it to develop more rapidly and be at a more advanced stage of development relative to the donor at the time of transplantation. The photomicrographs at the bottom of the figure show the fluorescent dextran-labeled graft (outlined in white) well integrated into the host. XAP-1 immunoreactivity (indicated by cross-hatched white area) is at the outer margin of the retina, where it abuts the retinal pigment epithelium (RPE). At the stage of initial XAP-1 expression the retina is still relatively immature and has yet to develop laminae. In the isochronic condition XAP-1 immunoreactivity is uninterrupted by the graft. In contrast, in the heterochronic condition XAP-1 expression stops abruptly at the borders of the older host with the younger graft.|
|Figure 2. (A) Illustrates the way Delta (Dl) and Notch (N) interact to produce lateral inhibition. Relative strength of signals is indicated by letter size and line thickness. One cell is biased to differentiate first (white cell on left), through either stochastic selection or intrinsic differences between progenitors and produces a high level of the ligand Delta, activating the Notch receptor on neighboring cells. The receiving cell (gray, on right) is inhibited from responding to inductive cues in the environment and does not differentiate. Through a feedback mechanism, the inhibited cell produces less Delta ligand and fails to inhibit its neighbods) from differentiating. (B) A representative section through a Stage 41 retina from a Xenopus tadpole injected at the 32-cell stage with Delta mRNA and stained for epitope-tagged Delta protein. Low-density misexpression of Delta by progenitors leads primarily to differentiation as ganglion cells (in GCL) and cones (in ONL). Abbreviations: GCL-ganglion cell layer, ONL-outer nuclear layer.|