Maintenance of neuroepithelial progenitor cells by Delta-Notch signalling in the embryonic chick retina.
BACKGROUND
Neurons of the vertebrate central nervous system (CNS) are generated sequentially over a prolonged period from dividing neuroepithelial progenitor cells. Some cells in the progenitor cell population continue to proliferate while others stop dividing and differentiate as neurons. The mechanism that maintains the balance between these two behaviours is not known, although previous work has implicated Delta-Notch signalling in the process.


RESULTS
In normal development, the proliferative layer of the neuroepithelium includes both nascent neurons that transiently express Delta-1 (Dl1), and progenitor cells that do not. Using retrovirus-mediated gene misexpression in the embryonic chick retina, we show that where progenitor cells are exposed to Dl1 signalling, they are prevented from embarking on neuronal differentiation. A converse effect is seen in cells expressing a dominant-negative form of Dl1, Dl1(dn), which we show renders expressing cells deaf to inhibitory signals from their neighbours. In a multicellular patch of neuroepithelium expressing Dl1(dn), essentially all progenitors stop dividing and differentiate prematurely as neurons, which can be of diverse types. Thus, Delta-Notch signalling controls a cell's choice between remaining as a progenitor and differentiating as a neuron.


CONCLUSIONS
Nascent retinal neurons, by expressing Dl1, deliver lateral inhibition to neighbouring progenitors; this signal is essential to prevent progenitors from entering the neuronal differentiation pathway. Lateral inhibition serves the key function of maintaining a balanced mixture of dividing progenitors and differentiating progeny. We propose that the same mechanism operates throughout the vertebrate CNS, enabling large numbers of neurons to be produced sequentially and adopt different characters in response to a variety of signals. A similar mechanism of lateral inhibition, mediated by Delta and Notch proteins, may regulate stem-cell function in other tissues.
Henrique
D
D
Imperial Cancer Research Fund, PO Box 123, 44 Lincoln's Inn Fields, London, WC2A 3PX, UK. d.henrique@icrf.icnet.uk
Hirsinger
E
E
Adam
J
J
Le Roux
I
I
Pourquié
O
O
Ish-Horowicz
D
D
Lewis
J
J
D000818:Animals; D002454:Cell Differentiation / Q000502:physiology; D002455:Cell Division; D002642:Chick Embryo; D047908:Intracellular Signaling Peptides and Proteins; D008565:Membrane Proteins / Q000502:physiology*; D009024:Morphogenesis; D009474:Neurons / Q000166:cytology*; D051881:Receptor, Notch1; D011956:Receptors, Cell Surface / Q000502:physiology*; D012160:Retina / Q000166:cytology* / Q000196:embryology; D015398:Signal Transduction; D013234:Stem Cells / Q000166:cytology*; D014157:Transcription Factors
D047908:Intracellular Signaling Peptides and Proteins; D008565:Membrane Proteins; D051881:Receptor, Notch1; D011956:Receptors, Cell Surface; D014157:Transcription Factors; C064045:delta protein