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Resolution of the Novel Immune-Type Receptor Gene Cluster in Zebrafish

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Resolution of the Novel Immune-Type Receptor Gene Cluster in Zebrafish Resolution of the novel immune-type receptor gene cluster in zebrafish Jeffrey A. Yoder*, Ronda T. Litman†, M. Gail Mueller†, Salil Desai‡, Kimberly P. Dobrinski§, Jennifer S. Montgomery§, Matthew P. Buzzeo§, Tatsuya Ota¶, Chris T. Amemiyaʈ, Nikolaus S. Trede**, Sheng Wei††, Julie Y. Djeu††, Sean Humphray‡‡, Kerstin Jekosch‡‡, Jose A. Hernandez Prada§§, David A. Ostrov§§, and Gary W. Litman†‡††¶¶ *Department of Molecular Biomedical Sciences, College of Veterinary Medicine, North Carolina State University, 4700 Hillsborough Street, Raleigh, NC 27606; †Department of Molecular Genetics, All Children’s Hospital, 801 Sixth Street South, St. Petersburg, FL 33701; ‡Department of Pediatrics, University of South Florida College of Medicine, University of South Florida͞All Children’s Hospital Children’s Research Institute, 830 First Street South, St. Petersburg, FL 33701; §Department of Biology, University of South Florida, 4202 East Fowler Avenue, SCA 110, Tampa, FL 33620; ¶Graduate University for Advanced Studies, School of Advanced Sciences, Department of Biosystems Science, Kamiyamaguchi 1560-35, Hayama, Kanagawa 240-0193, Japan; ʈGenome Resource Center, Virginia Mason Research Center, 1201 Ninth Avenue, Seattle, WA 98101; **Huntsman Cancer Institute, 2000 Circle of Hope, Salt Lake City, UT 84112; ††Immunology Program, H. Lee Moffitt Cancer Center and Research Institute, 12902 Magnolia Avenue, Tampa, FL 33612; ‡‡The Wellcome Trust Sanger Institute, Wellcome Trust Genome Campus, Hinxton, Cambridge CB10 1SA, United Kingdom; and §§Department of Pathology, Immunology, and Laboratory Medicine, University of Florida College of Medicine, 1600 Southwest Archer Road, Gainesville, FL 32610 Edited by Leonard A. Herzenberg, Stanford University School of Medicine, Stanford, CA, and approved September 16, 2004 (received for review July 20, 2004) The novel immune-type receptor (NITR) genes encode a unique the transmembrane region (7, 14). Several families of NITRs are multigene family of leukocyte regulatory receptors, which possess expressed abundantly in NK lines in bony fish that exhibit an extracellular Ig variable (V) domain and may function in innate alloreactive specificity (14, 15). immunity. Artificial chromosomes that encode zebrafish NITRs At this point, there is no comprehensive understanding of the have been assembled into a contig spanning Ϸ350 kb. Resolution actual numbers of NITR genes in a single species, the compo- of the complete NITR gene cluster has led to the identification of sition of the chromosomal locus͞loci at which they are encoded, eight previously undescribed families of NITRs and has revealed their overall organization, patterns of diversity, and the rela- the presence of C-type lectins within the locus. A maximum tionship of variation in NITR structure to that of the other Ig haplotype of 36 NITR genes (138 gene sequences in total) can be receptors that mediate immune recognition. The developmental grouped into 12 distinct families, including inhibitory and activat- genetics and other unique features of the zebrafish suggest that ing receptors. An extreme level of interindividual heterozygosity is it is an ideal model for understanding the function of novel genes reflected in allelic polymorphisms, haplotype variation, and family- such as the NITRs. The enormous level of complexity, as well as specific isoform complexity. In addition, the exceptional diversity the genetic, signaling, and other structural findings described of NITR sequences among species suggests divergent evolution of here, are entirely consistent with a role for these genes in the this multigene family with a birth-and-death process of member recognition of diverse determinants. genes. High-confidence modeling of Nitr V-domain structures re- veals a significant shift in the spatial orientation of the Ig fold, in Materials and Methods the region of highest interfamily variation, compared with Ig V Sequencing, Mapping, and Analysis of Gene Transcripts. P1 artificial domains. These studies resolve a complete immune gene cluster in chromosome (PAC) screening, RACE, cDNA sequencing, iden- zebrafish and indicate that the NITRs represent the most complex tification of sequence-tagged site (STS) markers, and radiation ͞ family of activating inhibitory surface receptors thus far described. hybrid mapping were carried out as described (13, 14). Partial mapping and sequencing of PACs (AB strain) and bacterial arge families of activating and inhibitory leukocyte regula- artificial chromosomes (BACs) (Tu¨bingen strain) were con- Ltory receptors have been characterized in human and mouse ducted through the Zebrafish Genome Project at the Sanger (1–5) and effect a number of functions relating to innate Institute, Cambridge, United Kingdom (www.sanger.ac.uk͞ immunity as well as the regulation of cell–cell interactions. The Projects͞D࿝rerio). The Otter system was used to manually mammalian Fc and natural killer (NK) receptors are the best annotate sequences based on publicly available protein, cDNA, characterized in terms of function of the activating͞inhibitory and EST resources by using BLAST (www.ncbi.nlm.nih.gov͞blast) receptor multigene families (1); additional families of these (16). ACEDB (www.acedb.org) was used to visualize the gathered receptors also have been described (5). The NK receptors are the most genetically diverse and include the killer Ig-type receptors (KIRs), which are encoded in a continuous gene complex on This paper was submitted directly (Track II) to the PNAS office. chromosome 19 in human, and the C-type lectin Ly49 receptor Abbreviations: NITR, novel immune-type receptor; V, variable; PAC, P1 artificial chromo- genes, which are encoded on chromosome 6 in mouse (6). NK some; BAC, bacterial artificial chromosome; ITAM, immunoreceptor tyrosine-based acti- ͞ vating motif; NK, natural killer; I, intermediate; ITIM, immunoreceptor tyrosine-based receptors effect self nonself recognition through interactions inhibition motif; TCR, T cell antigen receptor; HV, hypervariable region; CDR, complemen- with MHC I or MHC I-related products (2–4). Although KIRs tarity-determining region; STS, sequence-tagged site. and Ly49s are encoded by unrelated gene families and possess Data deposition: The PAC, BAC, STS, and cDNA sequences have been deposited in the structurally distinct ectodomains, they both effect similar func- GenBank and ZFIN databases [accession nos. AL591382 (BUSM1-105L16), AL591482 tions and use shared mechanisms of intracellular signaling. (BUSM1-116C14), AL591405 (BUSM1-125J23), AL591418 (BUSM1-139E19), AL592105 (BUSM1-150L22), AL591497 (BUSM1-173M20), AL591401 (BUSM1-175P12), AL591372 Both Ig- (7) and C-type lectin (8, 9) receptors, which share (BUSM1-178A3), AL591391 (BUSM1-186F8), AL691521 (BUSM1-186K12), AL591427 some structural features with mammalian NK receptors, have (BUSM1-219H16), AL591476 (BUSM1-263J20), AL732544 (BUSM1-6I1), AL591406 (BUSM1- been identified in several different genera of bony fish (10). The 213M14), AL591420 (BUSM1-221H6), AL844870 (BUSM1-169I8), AL954849 (DKEY-7N10), Ig-type receptors are encoded by novel immune-type receptor G68151 (STS-CRI0002), G68152 (STS-CRI0003), G68153 (STS-CRI0004), G68154 (STS- CRI0005), G68155 (STS-CRI0006), G68156 (STS-CRI0007), BV096859 (STS-CRI0009), (NITR) genes and typically possess Ig variable (V) and inter- AY570232 (nitr1o cDNA), AY570233 (nitr5 cDNA), AY570234 (nitr6b cDNA), AY570235 mediate (I) ectodomains (11), transmembrane regions, and (nitr7b cDNA), AY606016 (nitr7b splicing variant, partial cDNA), AY570236 (nitr8 cDNA), cytoplasmic immunoreceptor tyrosine-based inhibition motifs AY570237 (nitr9-long cDNA), and AY570238 (nitr9-short cDNA)]. (ITIMs) (12–14). Putative activating forms are structurally sim- ¶¶To whom correspondence should be addressed. E-mail: [email protected]. ilar but contain a positively charged amino acid residue within © 2004 by The National Academy of Sciences of the USA 15706–15711 ͉ PNAS ͉ November 2, 2004 ͉ vol. 101 ͉ no. 44 www.pnas.org͞cgi͞doi͞10.1073͞pnas.0405242101 Downloaded by guest on September 23, 2021 information and to manually create gene structures based on this spersion), and transcriptional orientation of various NITR genes supporting evidence (17). define a series of contigs that project a relatively compact locus, in which extensive interindividual differences are evident (Fig. Analysis of Activating Function. A nitr9-L cDNA was subcloned 1A and see below). This projected map is validated by a solved into pLF, which is derived from pcDNA3 (Invitrogen) and sequence contig encompassing three PACs (BUSM1-173M20, introduces an amino-terminal peptide signal sequence (from BUSM1-105L16, and BUSM1-150L22) and one BAC (DKEY- zebrafish Nitr3a) and a FLAG epitope tag (13). Transfection 7N10). Table 2, which is published as supporting information on through recombination of the viral vector SP11 with the WR the PNAS web site, describes the characterization of 11 addi- strain of vaccinia virus (18), fluorescence-activated cell sorter tional AB-line PACs that are predicted to overlap the BAC (FACS) analysis of FLAG-tagged NITRs (13), and redirected (DKEY-7N10). The intergenic distances between nitr12, nitr7a, cytolysis of the P815 (19) target have been described previously. nitr3d, nitr1d, nitr1j, nitr5, and nitr6c predict a minimum distance A human DAP12 cDNA (a gift from E. Vivier, Universite´dela between nitr12 and nitr6c of 329 kb and a maximum distance of Me´diterrane´e, Marseille-Luminy, France) was subcloned into 357 kb. A hypothetical
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