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    Craig Mello PhD

    TitleDistinguished Professor
    InstitutionUniversity of Massachusetts Medical School
    DepartmentProgram in Molecular Medicine
    AddressUniversity of Massachusetts Medical School
    368 Plantatoin Street, Suite AS5-2047
    Worcester MA 01605
    Phone508-856-1602
        Overview 
        Narrative

        Academic Background

        Blais University Chair in Molecular Medicine, Co-Director RNA Therapeutics Institute

        Dr. Craig C. Mello received his B.Sc. degree in Biochemistry from Brown University in 1982, and received his Ph.D. from Harvard University in 1990. From 1990 to 1994 he conducted postdoctoral research at the Fred Hutchinson Cancer Research Center in Seattle, WA. He has been a member of the University of Massachusetts Medical School faculty since 1995, and a Howard Hughes Medical Investigator since 2000. His pioneering research on RNAi, in collaboration with Dr. Andrew Fire, has been recognized with numerous awards culminating with the prestigious 2006 Nobel Prize in Physiology or Medicine.

        Regulation of gene expression during early embryogenesis in C. elegans

        Photo: Craig Mello Embryonic patterning in C. elegans begins during the first few divisions of the fertilized egg as sister cells become committed to distinct developmental fates. These early cell fate decisions are controlled by a small set of genes that together encode several basic developmental functions, including; (a) genes whose products organize the cytoskeleton and establish the initial polarity of the embryo, (b) genes that encode cell signaling pathways, (c) genes whose products regulate mRNA translation and protein stability, and (d) genes that encode positive and negative regulators of transcription. The long term goal of this lab is to better understand how these and other, as yet unidentified, genes function to coordinate the spatial and temporal patterning of the embryo. Our experimental approach employs classical and reverse genetic techniques, molecular biology and biochemistry.

        A powerful new tool for our studies of embryogenesis (and a new area of research interest for the laboratory) involves a reverse genetic method called RNA interference or simply "RNAi." This method is similar conceptually to "antisense" however the active agent appears to be double stranded RNA and the interference effect is remarkably specific, potent and long lived. RNAi is having a truly dramatic impact on research in this organism making it possible to easily induce "knock out" phenotypes for nearly all worm genes. We are now investigating the genetics of the interference mechanism in the hope that we can better understand and use this tool. Perhaps we will learn to transplant or activate similar genetic interference mechanisms in other organisims.

        For more information on Dr. Mello's research, visit his Howard Hughes website at: http://www.hhmi.org/research/investigators/mello.html

        Figure 1

        Figure Legend

        A 28-cell stage C. elegans embryo stained with Dapi to reveal nuclei (blue) and with a monoclonal antibody raised against the PIE-1 protein (red). The PIE-1 protein is observed in the fertilized egg and is sequentially restricted to the germline stem cell after each division in the embryo. PIE-1 functions to prevent the germ cell from differentiating in response to somatic determinants and signals which are actively patterning the embryo during this time. Understanding the localization and function of PIE-1 is a major goal of research in our laboratory.

        Figure 2

        Figure Legend

        A 2-cell C. elegans embryo divides to produce 4-cells in this series of images. On the left Nomarski microscopy reveals the grainy yolk droplets in the cytoplasm and the smooth circular nuclei in the center of the cells. On the right, the same embryos are imaged to visualize GFP (Green Fluorescent Protein) which has been tagged onto the PIE-1 protein. During this sequence of images, the PIE-1::GFP fusion protein first becomes nuclear, then during mitosis associates with the centrosome (middle panels), finally after cell division the protein re-enters the nucleus. PIE-1 functions to prevent the germ cell from differentiating in response to somatic determinants and signals which are actively patterning the embryo during this time. Understanding the localization and function of PIE-1 is a major goal of research in our laboratory. We are using this GFP construct to follow PIE-1 protein in mutant backgrounds and to determine what parts of the PIE-1 protein control its embryonic and subcellular localization.



        Rotation Projects

        Potential Rotation Projects:

        • Project #1: Identify and characterize genes that control cell fate and cell polarity during early C. elegans development.


        • Project #2: Identify and characterize genes that mediate RNAi.


        Bibliographic 
        selected publications
        List All   |   Timeline
        1. Ishidate T, Elewa A, Kim S, Mello CC, Shirayama M. Divide and differentiate: CDK/Cyclins and the art of development. Cell Cycle. 2014 May 1; 13(9):1384-91.
          View in: PubMed
        2. Seth M, Shirayama M, Gu W, Ishidate T, Conte D, Mello CC. The C. elegans CSR-1 argonaute pathway counteracts epigenetic silencing to promote germline gene expression. Dev Cell. 2013 Dec 23; 27(6):656-63.
          View in: PubMed
        3. Conine CC, Moresco JJ, Gu W, Shirayama M, Conte D, Yates JR, Mello CC. Argonautes Promote Male Fertility and Provide a Paternal Memory of Germline Gene Expression in C. elegans. Cell. 2013 Dec 19; 155(7):1532-44.
          View in: PubMed
        4. Ishidate T, Kim S, Mello C, Shirayama M. Inductive asymmetric cell division: The WRM leads the way. Worm. 2013 Oct 1; 2(4):e26276.
          View in: PubMed
        5. Kim S, Ishidate T, Sharma R, Soto MC, Conte D, Mello CC, Shirayama M. Wnt and CDK-1 regulate cortical release of WRM-1/ß-catenin to control cell division orientation in early Caenorhabditis elegans embryos. Proc Natl Acad Sci U S A. 2013 Mar 5; 110(10):E918-27.
          View in: PubMed
        6. Gu W, Lee HC, Chaves D, Youngman EM, Pazour GJ, Conte D, Mello CC. CapSeq and CIP-TAP identify Pol II start sites and reveal capped small RNAs as C. elegans piRNA precursors. Cell. 2012 Dec 21; 151(7):1488-500.
          View in: PubMed
        7. D'Ambrogio A, Gu W, Udagawa T, Mello CC, Richter JD. Specific miRNA stabilization by Gld2-catalyzed monoadenylation. Cell Rep. 2012 Dec 27; 2(6):1537-45.
          View in: PubMed
        8. Shirayama M, Seth M, Lee HC, Gu W, Ishidate T, Conte D, Mello CC. piRNAs initiate an epigenetic memory of nonself RNA in the C. elegans germline. Cell. 2012 Jul 6; 150(1):65-77.
          View in: PubMed
        9. Lee HC, Gu W, Shirayama M, Youngman E, Conte D, Mello CC. C. elegans piRNAs mediate the genome-wide surveillance of germline transcripts. Cell. 2012 Jul 6; 150(1):78-87.
          View in: PubMed
        10. Thivierge C, Makil N, Flamand M, Vasale JJ, Mello CC, Wohlschlegel J, Conte D, Duchaine TF. Tudor domain ERI-5 tethers an RNA-dependent RNA polymerase to DCR-1 to potentiate endo-RNAi. Nat Struct Mol Biol. 2012 Jan; 19(1):90-7.
          View in: PubMed
        11. Gu W, Claycomb JM, Batista PJ, Mello CC, Conte D. Cloning Argonaute-associated small RNAs from Caenorhabditis elegans. Methods Mol Biol. 2011; 725:251-80.
          View in: PubMed
        12. Xie J, Xie Q, Zhang H, Ameres SL, Hung JH, Su Q, He R, Mu X, Seher Ahmed S, Park S, Kato H, Li C, Mueller C, Mello CC, Weng Z, Flotte TR, Zamore PD, Gao G. MicroRNA-regulated, systemically delivered rAAV9: a step closer to CNS-restricted transgene expression. Mol Ther. 2011 Mar; 19(3):526-35.
          View in: PubMed
        13. Conte D, Mello CC. Primal RNAs: The end of the beginning? Cell. 2010 Feb 19; 140(4):452-4.
          View in: PubMed
        14. Conine CC, Batista PJ, Gu W, Claycomb JM, Chaves DA, Shirayama M, Mello CC. Argonautes ALG-3 and ALG-4 are required for spermatogenesis-specific 26G-RNAs and thermotolerant sperm in Caenorhabditis elegans. Proc Natl Acad Sci U S A. 2010 Feb 23; 107(8):3588-93.
          View in: PubMed
        15. Vasale JJ, Gu W, Thivierge C, Batista PJ, Claycomb JM, Youngman EM, Duchaine TF, Mello CC, Conte D. Sequential rounds of RNA-dependent RNA transcription drive endogenous small-RNA biogenesis in the ERGO-1/Argonaute pathway. Proc Natl Acad Sci U S A. 2010 Feb 23; 107(8):3582-7.
          View in: PubMed
        16. Liu J, Maduzia LL, Shirayama M, Mello CC. NMY-2 maintains cellular asymmetry and cell boundaries, and promotes a SRC-dependent asymmetric cell division. Dev Biol. 2010 Mar 15; 339(2):366-73.
          View in: PubMed
        17. Claycomb JM, Batista PJ, Pang KM, Gu W, Vasale JJ, van Wolfswinkel JC, Chaves DA, Shirayama M, Mitani S, Ketting RF, Conte D, Mello CC. The Argonaute CSR-1 and its 22G-RNA cofactors are required for holocentric chromosome segregation. Cell. 2009 Oct 2; 139(1):123-34.
          View in: PubMed
        18. Gu W, Shirayama M, Conte D, Vasale J, Batista PJ, Claycomb JM, Moresco JJ, Youngman EM, Keys J, Stoltz MJ, Chen CC, Chaves DA, Duan S, Kasschau KD, Fahlgren N, Yates JR, Mitani S, Carrington JC, Mello CC. Distinct argonaute-mediated 22G-RNA pathways direct genome surveillance in the C. elegans germline. Mol Cell. 2009 Oct 23; 36(2):231-44.
          View in: PubMed
        19. Batista PJ, Ruby JG, Claycomb JM, Chiang R, Fahlgren N, Kasschau KD, Chaves DA, Gu W, Vasale JJ, Duan S, Conte D, Luo S, Schroth GP, Carrington JC, Bartel DP, Mello CC. PRG-1 and 21U-RNAs interact to form the piRNA complex required for fertility in C. elegans. Mol Cell. 2008 Jul 11; 31(1):67-78.
          View in: PubMed
        20. Mello CC. Return to the RNAi world: rethinking gene expression and evolution. Cell Death Differ. 2007 Dec; 14(12):2013-20.
          View in: PubMed
        21. Mello CC. Return to the RNAi world: rethinking gene expression and evolution (Nobel Lecture). Angew Chem Int Ed Engl. 2007; 46(37):6985-94.
          View in: PubMed
        22. Yigit E, Batista PJ, Bei Y, Pang KM, Chen CC, Tolia NH, Joshua-Tor L, Mitani S, Simard MJ, Mello CC. Analysis of the C. elegans Argonaute family reveals that distinct Argonautes act sequentially during RNAi. Cell. 2006 Nov 17; 127(4):747-57.
          View in: PubMed
        23. Hayakawa A, Leonard D, Murphy S, Hayes S, Soto M, Fogarty K, Standley C, Bellve K, Lambright D, Mello C, Corvera S. The WD40 and FYVE domain containing protein 2 defines a class of early endosomes necessary for endocytosis. Proc Natl Acad Sci U S A. 2006 Aug 8; 103(32):11928-33.
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        24. Duchaine TF, Wohlschlegel JA, Kennedy S, Bei Y, Conte D, Pang K, Brownell DR, Harding S, Mitani S, Ruvkun G, Yates JR, Mello CC. Functional proteomics reveals the biochemical niche of C. elegans DCR-1 in multiple small-RNA-mediated pathways. Cell. 2006 Jan 27; 124(2):343-54.
          View in: PubMed
        25. Shirayama M, Soto MC, Ishidate T, Kim S, Nakamura K, Bei Y, van den Heuvel S, Mello CC. The Conserved Kinases CDK-1, GSK-3, KIN-19, and MBK-2 Promote OMA-1 Destruction to Regulate the Oocyte-to-Embryo Transition in C. elegans. Curr Biol. 2006 Jan 10; 16(1):47-55.
          View in: PubMed
        26. Nakamura K, Kim S, Ishidate T, Bei Y, Pang K, Shirayama M, Trzepacz C, Brownell DR, Mello CC. Wnt signaling drives WRM-1/beta-catenin asymmetries in early C. elegans embryos. Genes Dev. 2005 Aug 1; 19(15):1749-54.
          View in: PubMed
        27. Wang D, Kennedy S, Conte D, Kim JK, Gabel HW, Kamath RS, Mello CC, Ruvkun G. Somatic misexpression of germline P granules and enhanced RNA interference in retinoblastoma pathway mutants. Nature. 2005 Jul 28; 436(7050):593-7.
          View in: PubMed
        28. Chen CC, Simard MJ, Tabara H, Brownell DR, McCollough JA, Mello CC. A member of the polymerase beta nucleotidyltransferase superfamily is required for RNA interference in C. elegans. Curr Biol. 2005 Feb 22; 15(4):378-83.
          View in: PubMed
        29. Grigorenko AP, Moliaka YK, Soto MC, Mello CC, Rogaev EI. The Caenorhabditis elegans IMPAS gene, imp-2, is essential for development and is functionally distinct from related presenilins. Proc Natl Acad Sci U S A. 2004 Oct 12; 101(41):14955-60.
          View in: PubMed
        30. Mello CC, Conte D. Revealing the world of RNA interference. Nature. 2004 Sep 16; 431(7006):338-42.
          View in: PubMed
        31. Hutvágner G, Simard MJ, Mello CC, Zamore PD. Sequence-specific inhibition of small RNA function. PLoS Biol. 2004 Apr; 2(4):E98.
          View in: PubMed
        32. Pang KM, Ishidate T, Nakamura K, Shirayama M, Trzepacz C, Schubert CM, Priess JR, Mello CC. The minibrain kinase homolog, mbk-2, is required for spindle positioning and asymmetric cell division in early C. elegans embryos. Dev Biol. 2004 Jan 1; 265(1):127-39.
          View in: PubMed
        33. Venkatesan K, McManus HR, Mello CC, Smith TF, Hansen U. Functional conservation between members of an ancient duplicated transcription factor family, LSF/Grainyhead. Nucleic Acids Res. 2003 Aug 1; 31(15):4304-16.
          View in: PubMed
        34. Conte D, Mello CC. RNA interference in Caenorhabditis elegans. Curr Protoc Mol Biol. 2003 May; Chapter 26:Unit 26.3.
          View in: PubMed
        35. Unhavaithaya Y, Shin TH, Miliaras N, Lee J, Oyama T, Mello CC. MEP-1 and a homolog of the NURD complex component Mi-2 act together to maintain germline-soma distinctions in C. elegans. Cell. 2002 Dec 27; 111(7):991-1002.
          View in: PubMed
        36. Tabara H, Yigit E, Siomi H, Mello CC. The dsRNA binding protein RDE-4 interacts with RDE-1, DCR-1, and a DExH-box helicase to direct RNAi in C. elegans. Cell. 2002 Jun 28; 109(7):861-71.
          View in: PubMed
        37. Soto MC, Qadota H, Kasuya K, Inoue M, Tsuboi D, Mello CC, Kaibuchi K. The GEX-2 and GEX-3 proteins are required for tissue morphogenesis and cell migrations in C. elegans. Genes Dev. 2002 Mar 1; 16(5):620-32.
          View in: PubMed
        38. Grishok A, Mello CC. RNAi (Nematodes: Caenorhabditis elegans). Adv Genet. 2002; 46:339-60.
          View in: PubMed
        39. Grishok A, Pasquinelli AE, Conte D, Li N, Parrish S, Ha I, Baillie DL, Fire A, Ruvkun G, Mello CC. Genes and mechanisms related to RNA interference regulate expression of the small temporal RNAs that control C. elegans developmental timing. Cell. 2001 Jul 13; 106(1):23-34.
          View in: PubMed
        40. Grishok A, Tabara H, Mello CC. Genetic requirements for inheritance of RNAi in C. elegans. Science. 2000 Mar 31; 287(5462):2494-7.
          View in: PubMed
        41. Tabara H, Sarkissian M, Kelly WG, Fleenor J, Grishok A, Timmons L, Fire A, Mello CC. The rde-1 gene, RNA interference, and transposon silencing in C. elegans. Cell. 1999 Oct 15; 99(2):123-32.
          View in: PubMed
        42. Shin TH, Yasuda J, Rocheleau CE, Lin R, Soto M, Bei Y, Davis RJ, Mello CC. MOM-4, a MAP kinase kinase kinase-related protein, activates WRM-1/LIT-1 kinase to transduce anterior/posterior polarity signals in C. elegans. Mol Cell. 1999 Aug; 4(2):275-80.
          View in: PubMed
        43. Rocheleau CE, Yasuda J, Shin TH, Lin R, Sawa H, Okano H, Priess JR, Davis RJ, Mello CC. WRM-1 activates the LIT-1 protein kinase to transduce anterior/posterior polarity signals in C. elegans. Cell. 1999 Jun 11; 97(6):717-26.
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        44. Tabara H, Grishok A, Mello CC. RNAi in C. elegans: soaking in the genome sequence. Science. 1998 Oct 16; 282(5388):430-1.
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        45. Fire A, Xu S, Montgomery MK, Kostas SA, Driver SE, Mello CC. Potent and specific genetic interference by double-stranded RNA in Caenorhabditis elegans. Nature. 1998 Feb 19; 391(6669):806-11.
          View in: PubMed
        46. Rocheleau CE, Downs WD, Lin R, Wittmann C, Bei Y, Cha YH, Ali M, Priess JR, Mello CC. Wnt signaling and an APC-related gene specify endoderm in early C. elegans embryos. Cell. 1997 Aug 22; 90(4):707-16.
          View in: PubMed
        47. Mello C, Fire A. DNA transformation. Methods Cell Biol. 1995; 48:451-82.
          View in: PubMed
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