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Genetic and Molecular Characterization of a Notch

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Genetic and Molecular Characterization of a Notch Proc. Natl. Acad. Sci. USA Vol. 90, pp. 4037-4041, May 1993 Cell Biology Genetic and molecular characterization of a Notch mutation in its Delta- and Serrate-binding domain in Drosophila (protein-protein interactions/receptor-ligand complexes/cell signaling) JOSE F. DE CELIS*, ROSA BARRIO, ARACELI DEL ARCO, AND ANTONIO GARCfA-BELLIDOt Centro de Biologfa Molecular "Severo Ochoa," Universidad Aut6noma de Madrid, Cantoblanco, 28049 Madrid, Spain Contributed by Antonio Garcia-Bellido, January 11, 1993 ABSTRACT The DrosophUa Notch gene product is a trans- 14 (19). Ax and spl affect different subsets of developmental membrane protein that functions as a receptor of intercellular processes in which N is involved, in sensory organ mother- signals in several Drosophila developmental processes. Two cell specification (18, 20, 21) and wing vein differentiation (9). other transmembrane proteins, encoded by the genes Delta and These two classes of mutations could define N domains Serrate, genetically and molecularly behave as Notch ligands. involved in the modulation of both the binding of N with its AU these proteins share the presence of epidermal growth ligands and the subsequent activation of the N protein. A factor (EGF)-like repeats in their extracellular domain. The third class of N alleles, called notchoid (nd), due to amino Notch protein has 36 EGF-like repeats, 2 ofwhich, numbers 11 acid substitutions in the intracellular domain of the N protein and 12, are required for the interaction with the Delta and (22), causes insufficiencies of N function. Serrate ligands. We have isolated and molecularly character- Genetic studies have helped to identify other gene products ized a Notch mutation in its Delta- and Serrate-binding domain as candidates to interact with N protein (22-26). These that behaves genetically as both a Notch antimorphic and a include other transmembrane proteins with EGF repeats, loss-of-function mutation. This mutation, NM), carries a Glu -* such as Delta (Dl) (27, 28) and Serrate (Ser) (29, 30); secreted Val substitution in the Notch EGF repeat 12. The NM) allele proteins, such as scabrous (sca) (31); and nuclear proteins, interacts with other Notch alleles such as Abruptex and split including those encoded by Enhancer of split (E-spt) (32), and with mutations in the Notch-ligand genes Delta and groucho (gro) (33), mastermind (mam) (34), vestigial (vg) Serrate. The basis for the genetic antimorphism of NM) seems (35), and Hairless (H) (36, 37). In fact, in vitro cell adhesion to reside in the titration of Notch wild-type products into assays have shown direct protein-protein interactions be- NMl/N+ nonfunctional dimers and/or the titration of Delta tween N and Dl products and between N and Ser products products into nonfunctional ligand-receptor complexes. (16). The study of the ability of different truncated versions of the N protein in this in vitro assay has shown that its The Notch (N) gene is involved in various Drosophila EGF-like repeats 11 and 12 are necessary and sufficient for developmental processes and their mutations are therefore interaction with both Dl and Ser proteins in promoting cell pleiotropic (1, 2). The N function is required in both neural adhesion (16). (peripheral and central nervous system) and mesodermal We have found another type of N allele, called NM), that development (3-5), in many differentiation steps of omma- genetically behaves as an antimorphic, loss-of-function mu- tidia development (6), in somatic cell specification during tation of the N locus. This allele interacts with Ax, spl, Dl, oogenesis (7, 8), and in wing vein formation (9). and Ser mutations in a different way than a N null allele. The The Drosophila N product is a transmembrane protein with NM) mutation is associated with a Glu -* Val substitution in in its extra- EGF repeat 12, a region known to be involved in ligand 36 epidermal growth factor (EGF)-like repeats interactions (16). We will discuss how this molecular pertur- cellular domain and a large intracellular domain (10, 11). bation may explain NMi genetic behavior and the implications Extensive biochemical characterization of N protein has the N function. shown that N polypeptides exist as homodimers in the cell for mechanism of membrane (12). Genetic evidence is also compatible with N operating as a dimer molecule (13). The requirement for N MATERIALS AND METHODS function, as shown in genetic mosaics, is cell autonomous Genetic Strains. We have used the following alleles in the (reviewed in ref. 14). The molecular nature of the N gene N locus: the N null allele N55ell (38), the Ax viable alleles suggests that N protein participates in processes of cell-cell Ax'6172, AxE2, Ax17d, Ax28, and Ax9B2 (39-41), the Ax lethal communication. It has been proposed that N either partici- alleles AxMJ and AxM3 (9, 18), and the N recessive allelesfand, pates in a cell adhesion mechanism required to allow cell nd, and spl (1, 19, 22). We also used Dp(J;2)w+5b7 and interactions (15) or is a multiple-ligand receptor of intercel- Dp(l;Y)w+303 (41) as N gene duplications. lular signals (16). The mutations in the Dl locus used were the Dl lethal alleles The molecular characterization of different N mutations DiM) and DiM3 (42) and D19P39 (43), the Dl viable allele Dlvia3, has revealed a tight relationship between specific protein and the Dl+ duplication Dp(3;3)bxd"0 (43). The mutations in domains and genetic behavior. Thus, a class of N dominant other genes used were the Ser null alleles SerRx82 and alleles called Abruptex (Ax) (17), which cause a ligand- SerRx'06 (30), the E(spl) deletion E(spl)RA7' (32), the gro dependent hyperactivation of the N protein (18), are pro- lethal allele groE73 (33), the H mutations HM7 (42) and H2 (36), duced by different single amino acid substitutions scattered and the mam mutations mamN2G and mamKE272 (24). In some in the EGF repeats 23-25 of its extracellular domain (13, 19). experiments we also used the recombinant chromosomes The split (spi) recessive allele, which also produces a hyper- activation of the N protein (20), maps in the EGF-like repeat Abbreviations: EGF, epidermal growth factor; SSCP, single-strand conformation polymorphism. The publication costs of this article were defrayed in part by page charge *Present address: Department ofGenetics, University ofCambridge, payment. This article must therefore be hereby marked "advertisement" Downing Street, Cambridge CB2 3EH, England. in accordance with 18 U.S.C. §1734 solely to indicate this fact. tTo whom reprint requests should be addressed. 4037 Downloaded by guest on September 24, 2021 4038 Cefl Biology: de Celis et aL Proc. Natl. Acad. Sci. USA 90 (1993) DlM2HM7 (42) and D19P32H2 (24). The Vallecas strain, in which Cloning and Sequencing. PCR products from wild-type and the mutation NM) arose in a mutagenesis experiment with mutant DNA were subcloned in the Sma I site ofpUC18 (47). ethyl methanesulfonate (44), was used as wild-type control. Twelve independent clones from mutant flies (derived from DNA Polymerase Chain Reaction (PCR) and Single-Strand three different PCRs) and two clones from wild-type DNA Conformation Polymorphism (SSCP) Analyses. Genomic were sequenced by using a Sequenase kit (United States DNA was prepared (45) from NMi heterozygous females and Biochemical) and pUC18 primers. from parental Vallecas wild-type females as controls. PCR was performed (46) with 25 pmol of the following primers, RESULTS derived from sequences within the EGF-like motifs 10 and 13 ofthe N protein (11): 5'-TGACACGAGTCCGATAAACG-3' Characterization of a N Antimorphic Mutation. The muta- and 5'-AAGTTCCATCGTTCAGG-3'. For the SSCP gel tion NM) was isolated in an ethyl methanesulfonate muta- analysis the PCR step was performed as described above, genesis screen, as a female presenting a stronger than usual including 0.1 ,u of [a-32P]dCTP (3000 Ci/ml; 1 Ci = 37 GBq). dominant N phenotype (Fig. 1 A and B). Hemizygous NM) PCR products were denatured and loaded onto nondenatur- individuals die as embryos, displaying a severe neurogenic ing 7% polyacrylamide gels (25:1 acrylamide/methylenebis phenotype (48) as revealed by the absence of ventral cuticle acrylamide weight ratio). Electrophoresis was carried out at and the presence of a hyperplasic central nervous system constant power (20 W) in the cold room. (data not shown). The allelism of NM) to the N locus was E G of combinations of 4ssell (A, C, E, and G) and NMI (B, D, F, and H) with genetic variants in the N and FIG. 1. Wing phenotypes genetic allele). Ser genes. (A and B) Heterozygous females. (C and D) Heterozygotes over Ax28 (N-S allele). (E and F) Heterozygotes over AX16172 (N-E (F and G) Doubly heterozygous N and SerPx"06 females. All wings are shown at the same magnification. Downloaded by guest on September 24, 2021 Cell Biology: de Celis et al. Proc. Natl. Acad. Sci. USA 90 (1993) 4039 further confirmed in combinations with the N recessive alleles. Thus, heterozygous females that are NM)/nd and NMlIfand are poorly viable, and those that survive show strong nd andfand phenotypes. The lethality of NMi males is rescued by a N+ duplication, but the corresponding adults still retain a weak N phenotype, consisting ofdistal wing vein thickening and cuts in the wing margin. This contrasts with N-/Dp N+ males, which are phenotypically wild type. Taken together these results indicate that NM) is a mutation at the N locus that genetically behaves as a loss-of-function antimorphic mutation. According to the view of N proteins acting as dimers (12), NM) may produce an altered N protein that forms inactive dimers with N+ proteins. The antimor- phism could then result from: (i) sequestering of N+ proteins by NM1 ones in inactive N+/NMl dimers or (ii) competition between N+ and NM1 proteins forthe N ligands, ifligand-NMl complexes are nonfunctional.
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