Mutation of the Diamond-Blackfan Anemia Gene in Mouse Results in Morphological and Neuroanatomical Phenotypes

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The ribosome is an evolutionarily conserved organelle essential for cellular function. Ribosome construction requires assembly of approximately 80 different ribosomal proteins (RPs) and four different species of rRNA. As RPs co-assemble into one multi-subunit complex, mutation of the genes that encode RPs might be expected to give rise to phenocopies, in which the same phenotype is associated with loss-of-function of each individual gene. However, a more complex picture is emerging in which, in addition to a group of shared phenotypes, diverse RP gene-specific phenotypes are observed. Here we report the first two mouse mutations (Rps7^Mtu and Rps7^Zma) of ribosomal protein S7 (Rps7), a gene that has been implicated in Diamond-Blackfan anemia. Rps7 disruption results in decreased body size, abnormal skeletal morphology, mid-ventral white spotting, and eye malformations. These phenotypes are reported in other murine RP mutants and, as demonstrated for some other RP mutations, are ameliorated by Trp53 deficiency. Interestingly, Rps7 mutants have additional overt malformations of the developing central nervous system and deficits in working memory, phenotypes that are not reported in murine or human RP gene mutants. Conversely, Rps7 mouse mutants show no anemia or hyperpigmentation, phenotypes associated with mutation of human RPS7 and other murine RPs, respectively. We provide two novel RP mouse models and expand the repertoire of potential phenotypes that should be examined in RP mutants to further explore the concept of RP gene-specific phenotypes.

Vyšlo v časopise: Mutation of the Diamond-Blackfan Anemia Gene in Mouse Results in Morphological and Neuroanatomical Phenotypes. PLoS Genet 9(1): e32767. doi:10.1371/journal.pgen.1003094
Kategorie: Research Article
prolekare.web.journal.doi_sk: https://doi.org/10.1371/journal.pgen.1003094

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1. UechiT, TanakaT, KenmochiN (2001) A complete map of the human ribosomal protein genes: assignment of 80 genes to the cytogenetic map and implications for human disorders. Genomics 72: 223–230 doi:10.1006/geno.2000.6470.

2. BoisvertF-M, van KoningsbruggenS, NavascuésJ, LamondAI (2007) The multifunctional nucleolus. Nat Rev Mol Cell Biol 8: 574–585 doi:10.1038/nrm2184.

3. MarygoldSJ, RooteJ, ReuterG, LambertssonA, AshburnerM, et al. (2007) The ribosomal protein genes and Minute loci of Drosophila melanogaster. Genome Biol 8: R216 doi:10.1186/gb-2007-8-10-r216.

4. UechiT, NakajimaY, NakaoA, ToriharaH, ChakrabortyA, et al. (2006) Ribosomal protein gene knockdown causes developmental defects in zebrafish. PLoS ONE 1: e37 doi:10.1371/journal.pone.0000037.

5. McgowanKA, LiJZ, ParkCY, BeaudryV, TaborHK, et al. (2008) Ribosomal mutations cause p53-mediated dark skin and pleiotropic effects. Nat Genet 40: 963–970 doi:10.1038/ng.188.

6. OliverER, SaundersTL, TarléSA, GlaserT (2004) Ribosomal protein L24 defect in belly spot and tail (Bst), a mouse Minute. Development 131: 3907–3920 doi:10.1242/dev.01268.

7. TerzianT, DumbleM, ArbabF, ThallerC, DonehowerLA, et al. (2011) Rpl27a mutation in the sooty foot ataxia mouse phenocopies high p53 mouse models. J Pathol 224: 540–552 doi:10.1002/path.2891.

8. FarrarJE, NaterM, CaywoodE, McDevittMA, KowalskiJ, et al. (2008) Abnormalities of the large ribosomal subunit protein, Rpl35a, in Diamond-Blackfan anemia. Blood 112: 1582–1592 doi:10.1182/blood-2008-02-140012.

9. GazdaHT, GrabowskaA, Merida-LongLB, LatawiecE, SchneiderHE, et al. (2006) Ribosomal protein S24 gene is mutated in Diamond-Blackfan anemia. Am J Hum Genet 79: 1110–1118 doi:10.1086/510020.

10. DohertyL, SheenMR, VlachosA, ChoesmelV, O'DonohueM-F, et al. (2010) Ribosomal protein genes RPS10 and RPS26 are commonly mutated in Diamond-Blackfan anemia. Am J Hum Genet 86: 222–228 doi:10.1016/j.ajhg.2009.12.015.

11. GazdaHT, SheenMR, VlachosA, ChoesmelV, O'DonohueM-F, et al. (2008) Ribosomal protein L5 and L11 mutations are associated with cleft palate and abnormal thumbs in Diamond-Blackfan anemia patients. Am J Hum Genet 83: 769–780 doi:10.1016/j.ajhg.2008.11.004.

12. GazdaHT, PretiM, SheenMR, O'DonohueM-F, VlachosA, et al. (2012) Frameshift mutation in p53 regulator RPL26 is associated with multiple physical abnormalities and a specific pre-ribosomal RNA processing defect in diamond-blackfan anemia. Hum Mutat doi:10.1002/humu.22081.

13. CmejlaR, CmejlovaJ, HandrkovaH, PetrakJ, PospisilovaD (2007) Ribosomal protein S17 gene (RPS17) is mutated in Diamond-Blackfan anemia. Hum Mutat 28: 1178–1182 doi:10.1002/humu.20608.

14. DraptchinskaiaN, GustavssonP, AnderssonB, PetterssonM, WilligTN, et al. (1999) The gene encoding ribosomal protein S19 is mutated in Diamond-Blackfan anaemia. Nat Genet 21: 169–175 doi:10.1038/5951.

15. NolanPM, PetersJ, StrivensM, RogersD, HaganJ, et al. (2000) A systematic, genome-wide, phenotype-driven mutagenesis programme for gene function studies in the mouse. Nat Genet 25: 440–443 doi:10.1038/78140.

16. BoganiD, WarrN, ElmsP, DaviesJ, Tymowska-LalanneZ, et al. (2004) New semidominant mutations that affect mouse development. Genesis 40: 109–117 doi:10.1002/gene.20071.

17. MateraI, Watkins-ChowDE, LoftusSK, HouL, IncaoA, et al. (2008) A sensitized mutagenesis screen identifies Gli3 as a modifier of Sox10 neurocristopathy. Hum Mol Genet 17: 2118–2131 doi:10.1093/hmg/ddn110.

18. ThomasPD, KejariwalA, GuoN, MiH, CampbellMJ, et al. (2006) Applications for protein sequence-function evolution data: mRNA/protein expression analysis and coding SNP scoring tools. Nucleic Acids Res 34: W645–W650.

19. KumarP, HenikoffS, NgPC (2009) Predicting the effects of coding non-synonymous variants on protein function using the SIFT algorithm. Nat Protoc 4: 1073–1081 doi:10.1038/nprot.2009.86.

20. RablJ, LeibundgutM, AtaideSF, HaagA, BanN (2011) Crystal structure of the eukaryotic 40S ribosomal subunit in complex with initiation factor 1. Science 331: 730–736 doi:10.1126/science.1198308.

21. Ben-ShemA, Garreau de LoubresseN, MelnikovS, JennerL, YusupovaG, et al. (2011) The structure of the eukaryotic ribosome at 3.0 Å resolution. Science 334: 1524–1529 doi:10.1126/science.1212642.

22. RostB, YachdavG, LiuJ (2004) The PredictProtein server. Nucleic Acids Res 32: W321–W326 doi:10.1093/nar/gkh377.

23. AngeliniM, CannataS, MercaldoV, GibelloL, SantoroC, et al. (2007) Missense mutations associated with Diamond-Blackfan anemia affect the assembly of ribosomal protein S19 into the ribosome. Hum Mol Genet 16: 1720–1727 doi:10.1093/hmg/ddm120.

24. RobledoS, IdolRA, CrimminsDL, LadensonJH, MasonPJ, et al. (2008) The role of human ribosomal proteins in the maturation of rRNA and ribosome production. RNA 14: 1918–1929 doi:10.1261/rna.1132008.

25. O'DonohueM-F, ChoesmelV, FaubladierM, FichantG, GleizesP-E (2010) Functional dichotomy of ribosomal proteins during the synthesis of mammalian 40S ribosomal subunits. J Cell Biol 190: 853–866 doi:10.1083/jcb.201005117.

26. BowmanLH, RabinB, SchlessingerD (1981) Multiple ribosomal RNA cleavage pathways in mammalian cells. Nucleic Acids Res 9: 4951–4966.

27. DianzaniI, LoreniF (2008) Diamond-Blackfan anemia: a ribosomal puzzle. Haematologica 93: 1601–1604 doi:10.3324/haematol.2008.000513.

28. SocolovskyM, NamH, FlemingMD, HaaseVH, BrugnaraC, et al. (2001) Ineffective erythropoiesis in Stat5a(−/−)5b(−/−) mice due to decreased survival of early erythroblasts. Blood 98: 3261–3273.

29. ZhangJ, SocolovskyM, GrossAW, LodishHF (2003) Role of Ras signaling in erythroid differentiation of mouse fetal liver cells: functional analysis by a flow cytometry-based novel culture system. Blood 102: 3938–3946 doi:10.1182/blood-2003-05-1479.

30. PotterfSB, MollaaghababaR, HouL, Southard-SmithEM, HornyakTJ, et al. (2001) Analysis of SOX10 function in neural crest-derived melanocyte development: SOX10-dependent transcriptional control of dopachrome tautomerase. Dev Biol 237: 245–257 doi:10.1006/dbio.2001.0372.

31. DeaconRMJ, RawlinsJNP (2006) T-maze alternation in the rodent. Nat Protoc 1: 7–12 doi:10.1038/nprot.2006.2.

32. ChakrabortyA, UechiT, HigaS, ToriharaH, KenmochiN (2009) Loss of ribosomal protein L11 affects zebrafish embryonic development through a p53-dependent apoptotic response. PLoS ONE 4: e4152 doi:10.1371/journal.pone.0004152.

33. GazdaHT, KhoAT, SanoudouD, ZauchaJM, KohaneIS, et al. (2006) Defective ribosomal protein gene expression alters transcription, translation, apoptosis, and oncogenic pathways in Diamond-Blackfan anemia. Stem Cells 24: 2034–2044 doi:10.1634/stemcells.2005-0554.

34. MatssonH, DaveyEJ, DraptchinskaiaN, HamaguchiI, OokaA, et al. (2004) Targeted disruption of the ribosomal protein S19 gene is lethal prior to implantation. Mol Cell Biol 24: 4032–4037.

35. BarkićM, CrnomarkovićS, GrabusićK, BogetićI, PanićL, et al. (2009) The p53 tumor suppressor causes congenital malformations in Rpl24-deficient mice and promotes their survival. Mol Cell Biol 29: 2489–2504 doi:10.1128/MCB.01588-08.

36. ToriharaH, UechiT, ChakrabortyA, ShinyaM, SakaiN, et al. (2011) Erythropoiesis failure due to RPS19 deficiency is independent of an activated Tp53 response in a zebrafish model of Diamond-Blackfan anaemia. Br J Haematol 152: 648–654 doi:10.1111/j.1365-2141.2010.08535.x.

37. SulicS, PanićL, BarkićM, MercepM, UzelacM, et al. (2005) Inactivation of S6 ribosomal protein gene in T lymphocytes activates a p53-dependent checkpoint response. Genes Dev 19: 3070–3082 doi:10.1101/gad.359305.

38. WildT, HorvathP, WylerE, WidmannB, BadertscherL, et al. (2010) A protein inventory of human ribosome biogenesis reveals an essential function of exportin 5 in 60S subunit export. PLoS Biol 8: e1000522 doi:10.1371/journal.pbio.1000522.

39. SynetosD, DabevaMD, WarnerJR (1992) The yeast ribosomal protein S7 and its genes. J Biol Chem 267: 3008–3013.

40. SteffenKK, McCormickMA, PhamKM, MacKayVL, DelaneyJR, et al. (2012) Ribosome Deficiency Protects Against ER Stress in Saccharomyces cerevisiae. Genetics 191: 107–118 doi:10.1534/genetics.111.136549.

41. BernsteinKA, GallagherJEG, MitchellBM, GrannemanS, BasergaSJ (2004) The Small-Subunit Processome Is a Ribosome Assembly Intermediate. Eukaryotic Cell 3: 1619–1626 doi:10.1128/EC.3.6.1619-1626.2004.

42. Ferreira-CercaS, PöllG, GleizesP-E, TschochnerH, MilkereitP (2005) Roles of Eukaryotic Ribosomal Proteins in Maturation and Transport of Pre-18S rRNA and Ribosome Function. Molecular Cell 20: 263–275 doi:10.1016/j.molcel.2005.09.005.

43. GoodmanFR (2003) Congenital abnormalities of body patterning: embryology revisited. Lancet 362: 651–662 doi:10.1016/S0140-6736(03)14187-6.

44. BoganiD, WilloughbyC, DaviesJ, KaurK, MirzaG, et al. (2005) Dissecting the genetic complexity of human 6p deletion syndromes by using a region-specific, phenotype-driven mouse screen. Proc Natl Acad Sci USA 102: 12477–12482 doi:10.1073/pnas.0500584102.

45. MatssonH, DaveyEJ, FröjmarkAS, MiyakeK, UtsugisawaT, et al. (2006) Erythropoiesis in the Rps19 disrupted mouse: Analysis of erythropoietin response and biochemical markers for Diamond-Blackfan anemia. Blood Cells Mol Dis 36: 259–264 doi:10.1016/j.bcmd.2005.12.002.

46. MorganWC (1950) A new tail-short mutation in the mouse whose lethal effects are conditioned by the residual genotypes. J Hered 41: 208–215.

47. KondrashovN, PusicA, StumpfCR, ShimizuK, HsiehAC, et al. (2011) Ribosome-mediated specificity in Hox mRNA translation and vertebrate tissue patterning. Cell 145: 383–397 doi:10.1016/j.cell.2011.03.028.

48. SouthardJ, EischerE (1977) Belly spot and tail (Bst). Mouse News Letter 56: 40.

49. AndersonSJ, LauritsenJPH, HartmanMG, FousheeAMD, LefebvreJM, et al. (2007) Ablation of ribosomal protein L22 selectively impairs alphabeta T cell development by activation of a p53-dependent checkpoint. Immunity 26: 759–772 doi:10.1016/j.immuni.2007.04.012.

50. StadanlickJE, ZhangZ, LeeS-Y, HemannM, BieryM, et al. (2011) Developmental arrest of T cells in Rpl22-deficient mice is dependent upon multiple p53 effectors. J Immunol 187: 664–675 doi:10.4049/jimmunol.1100029.

51. Vlachos A, Ball S, Dahl N, Alter BP, Sheth S, et al.. (2008) Diagnosing and treating Diamond Blackfan anaemia: results of an international clinical consensus conference. Vol. 142. pp. 859–876. doi:10.1111/j.1365-2141.2008.07269.x.

52. TangYP, WadeJ (2010) Sex- and age-related differences in ribosomal proteins L17 and L37, as well as androgen receptor protein, in the song control system of zebra finches. Neuroscience 171: 1131–1140 doi:10.1016/j.neuroscience.2010.10.014.

53. FumagalliS, IvanenkovVV, TengT, ThomasG (2012) Suprainduction of p53 by disruption of 40S and 60S ribosome biogenesis leads to the activation of a novel G2/M checkpoint. Genes Dev 26: 1028–1040 doi:10.1101/gad.189951.112.

54. DuanJ, BaQ, WangZ, HaoM, LiX, et al. (2011) Knockdown of ribosomal protein S7 causes developmental abnormalities via p53 dependent and independent pathways in zebrafish. The International Journal of Biochemistry & Cell Biology 43: 1218–1227 doi:10.1016/j.biocel.2011.04.015.

55. WarnerJR, McIntoshKB (2009) How common are extraribosomal functions of ribosomal proteins? Molecular Cell 34: 3–11 doi:10.1016/j.molcel.2009.03.006.

56. BortoluzziS, d'AlessiF, RomualdiC, DanieliGA (2001) Differential expression of genes coding for ribosomal proteins in different human tissues. Bioinformatics 17: 1152–1157.

57. BévortM, LeffersH (2000) Down regulation of ribosomal protein mRNAs during neuronal differentiation of human NTERA2 cells. Differentiation 66: 81–92 doi:10.1046/j.1432-0436.2000.660203.x.

58. TerzianT, TorchiaEC, DaiD, RobinsonSE, MuraoK, et al. (2010) p53 prevents progression of nevi to melanoma predominantly through cell cycle regulation. Pigment Cell & Melanoma Research 23: 781–794 doi:10.1111/j.1755-148X.2010.00773.x.

59. KapasiP, ChaudhuriS, VyasK, BausD, KomarAA, et al. (2007) L13a Blocks 48S Assembly: Role of a General Initiation Factor in mRNA-Specific Translational Control. Molecular Cell 25: 113–126 doi:10.1016/j.molcel.2006.11.028.

60. SatoY, YanoS, EwisAA, NakahoriY (2011) SRY interacts with ribosomal proteins S7 and L13a in nuclear speckles. Cell Biology International 35: 449–452 doi:10.1042/CBI20090201.

61. WilkinsonDG, NietoMA (1993) Detection of messenger RNA by in situ hybridization to tissue sections and whole mounts. Meth Enzymol 225: 361–373.

62. Phan Dinh TuyF, SaillourY, KappelerC, ChellyJ, FrancisF (2008) Alternative transcripts of Dclk1 and Dclk2 and their expression in doublecortin knockout mice. Dev Neurosci 30: 171–186 doi:10.1159/000109861.

63. HennigJ, NauerthA, FriedburgH (1986) RARE imaging: a fast imaging method for clinical MR. Magn Reson Med 3: 823–833.

64. Paxinos G, Halliday GM, Watson C, Koutcherov Y, Wang H (2006) Atlas of the Developing Mouse Brain at E17.5, P0 and P6. Academic Press.