cis-Inhibition of Notch by endogenous Delta biases the outcome of lateral inhibition.
Lateral inhibition mediated by Delta/Notch (Dl/N) signaling is used throughout development to limit the number of initially equivalent cells that adopt a particular fate. Although adjacent cells express both Dl ligand and N receptor, signaling between them ultimately occurs in only one direction. Classically, this has been explained entirely by feedback: activated N can downregulate Dl, amplifying even slight asymmetries in the Dl or N activities of adjacent cells. Here, however, we present an example of lateral inhibition in which unidirectional signaling depends instead on Dl's ability to inhibit N within the same cell, a phenomenon known as cis-inhibition. By genetically manipulating individual R1/R6/R7 photoreceptor precursors in the Drosophila eye, we show that loss of Dl-mediated cis-inhibition reverses the direction of lateral signaling. Based on our finding that Dl in R1/R6s requires endocytosis to trans-activate but not to cis-inhibit N, we reexamine previously published data from other examples of lateral inhibition. We conclude that cis-inhibition generally influences the direction of Dl/N signaling and should therefore be included in standard models of lateral inhibition.
Miller
Adam C
AC
Institute of Molecular Biology, University of Oregon, Eugene, OR 97403, USA.
Lyons
Eric L
EL
Herman
Tory G
TG
D000818:Animals; D002450:Cell Communication; D019070:Cell Lineage; D054910:Compound Eye, Arthropod / Q000166:cytology / Q000254:growth & development*; D029721:Drosophila Proteins / Q000502:physiology*; D004331:Drosophila melanogaster / Q000166:cytology / Q000235:genetics / Q000254:growth & development*; D004705:Endocytosis; D004815:Epidermal Growth Factor / Q000502:physiology; D025461:Feedback, Physiological; D047908:Intracellular Signaling Peptides and Proteins; D007814:Larva; D008565:Membrane Proteins / Q000235:genetics / Q000502:physiology*; D008954:Models, Biological; D017956:Photoreceptor Cells, Invertebrate / Q000166:cytology* / Q000378:metabolism; D051880:Receptors, Notch / Q000502:physiology*; D015398:Signal Transduction / Q000502:physiology
D029721:Drosophila Proteins; D047908:Intracellular Signaling Peptides and Proteins; D008565:Membrane Proteins; C497759:N protein, Drosophila; D051880:Receptors, Notch; C064045:delta protein; D004815:Epidermal Growth Factor