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cis-Inhibition of Notch by Endogenous Delta Biases the Outcome of Lateral Inhibition

2009; Elsevier BV; Volume: 19; Issue: 16 Linguagem: Inglês

10.1016/j.cub.2009.06.042

1879-0445

Adam C. Miller, Eric L. Lyons, Tory Herman,

Hippo pathway signaling and YAP/TAZ

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 [1Artavanis-Tsakonas S. Rand M.D. Lake R.J. Notch signaling: Cell fate control and signal integration in development.Science. 1999; 284: 770-776Crossref PubMed Scopus (4667) Google Scholar, 2Baker N.E. Notch signaling in the nervous system. Pieces still missing from the puzzle.Bioessays. 2000; 22: 264-273Crossref PubMed Scopus (79) Google Scholar, 3Bray S.J. Notch signalling: A simple pathway becomes complex.Nat. Rev. Mol. Cell Biol. 2006; 7: 678-689Crossref PubMed Scopus (1814) Google Scholar]. 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 [1Artavanis-Tsakonas S. Rand M.D. Lake R.J. Notch signaling: Cell fate control and signal integration in development.Science. 1999; 284: 770-776Crossref PubMed Scopus (4667) Google Scholar, 2Baker N.E. Notch signaling in the nervous system. Pieces still missing from the puzzle.Bioessays. 2000; 22: 264-273Crossref PubMed Scopus (79) Google Scholar, 3Bray S.J. Notch signalling: A simple pathway becomes complex.Nat. Rev. Mol. Cell Biol. 2006; 7: 678-689Crossref PubMed Scopus (1814) Google Scholar, 4Heitzler P. Simpson P. The choice of cell fate in the epidermis of Drosophila.Cell. 1991; 64: 1083-1092Abstract Full Text PDF PubMed Scopus (572) Google Scholar, 5Wilkinson H.A. Fitzgerald K. Greenwald I. Reciprocal changes in expression of the receptor lin-12 and its ligand lag-2 prior to commitment in a C. elegans cell fate decision.Cell. 1994; 79: 1187-1198Abstract Full Text PDF PubMed Scopus (209) Google Scholar]. 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 [6Micchelli C.A. Rulifson E.F. Blair S.S. The function and regulation of Cut expression on the wing margin of Drosophila: Notch, Wingless and a dominant negative role for Delta and Serrate.Development. 1997; 124: 1485-1495Crossref PubMed Google Scholar, 7Klein T. Brennan K. Arias A.M. An intrinsic dominant negative activity of serrate that is modulated during wing development in Drosophila.Dev. Biol. 1997; 189: 123-134Crossref PubMed Scopus (110) Google Scholar, 8Jacobsen T.L. Brennan K. Arias A.M. Muskavitch M.A.T. Cis-interactions between Delta and Notch modulate neurogenic signalling in Drosophila.Development. 1998; 125: 4531-4540Crossref PubMed Google Scholar, 9Sakamoto K. Ohara O. Takagi M. Takeda S. Katsube K. Intracellular cell-autonomous association of Notch and its ligands: A novel mechanism of Notch signal modification.Dev. Biol. 2002; 241: 313-326Crossref PubMed Scopus (113) Google Scholar, 10Ladi E. Nichols J.T. Ge W. Miyamoto A. Yao C. Yang L.T. Boulter J. Sun Y.E. Kintner C. Weinmaster G. The divergent DSL ligand Dll3 does not activate Notch signaling but cell autonomously attenuates signaling induced by other DSL ligands.J. Cell Biol. 2005; 170: 983-992Crossref PubMed Scopus (200) Google Scholar, 11Cordle J. Johnson S. Tay J.Z. Roversi P. Wilkin M.B. de Madrid B.H. Shimizu H. Jensen S. Whiteman P. Jin B. et al.A conserved face of the Jagged/Serrate DSL domain is involved in Notch trans-activation and cis-inhibition.Nat. Struct. Mol. Biol. 2008; 15: 849-857Crossref PubMed Scopus (176) Google Scholar]. 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.