Postdoctoral Position Available

Craig Mello, Ph.D.

Academic Role: Professor

Faculty Appointment(s) In:
   Program in Molecular Medicine

Other Affiliation(s):
   Cancer Center
   Cell Biology
   Cell Dynamics Group
   Center for AIDS Research
   Interdisciplinary Graduate Program

Regulation of gene expression during early embryogenesis in C. elegans

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 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 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.

Recent Publications

Nakamura, K., Kim, S., Ishidate, T., Bei, Y., Pang, K-M, Shirayama, M., Trzepacz, C., Brownell, D.R., Mello, C.C. (2005)  Wnt signaling drives WRM-1/ß-catenin asymmetries in early C. elegans embryos.  Genes Dev. 2005 Aug 1;19(15);1749-54.

Wang, D., Kennedy, S., Conte Jr., D., Kim, J.K., Gabel, H.W., Kamath, R., Mello, C.C., Ruvkun, G., (2005). Somatic misexpression of germline P granules and enhanced RNA interference in retinoblastoma pathway mutants.  Nature July 28; 436(7050) 593-7.

Shirayama, M., Soto, M.C., Ishidate, T., Kim, S., Nakamura, K., Bei, Y., van den Heuvel, S., Mello, C.C. (2006) 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.  Current Biology Jan 10;16(1):47-55

Duchaine, T.F., Wohlschlegel,  J.A., Kennedy, S., Bei, Y., Conte, D., Pang, K-M., Brownell, D.R., Harding, S., Mitani, S., Ruvkun, G., Yates, J.R. Mello, C.C.  (2006)  Functional proteomics reveals the biochemical niche of C. elegans DCR-1 in multiple small-RNA-mediated pathways. Cell Jan 27;124(2):343-54.

Yigit, Y., Batista, P.J., Bei, Y., Pang, K-M., Chen, C-C.G., Tolia, N.H., Joshua-Tor, L., Mitani, S., Simard, M.J., Mello, C.C. (2006)  Analysis of the C. elegans Argonaute family reveals that distinct Argonautes Act Sequentially During RNAi.  Cell 127 November 12, 747-757.

Mello, C.C. (2007) Return to the RNAi World:  Rethinking Gene Expression and Evolution. (Nobel Lecture) Angewandte Chemie Int. Ed. 2007, 46, 6985-6994.

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.

Laboratory Personnel

Assistant Professors:  Darryl Conte, Ph.D., Masaki Shirayama, Ph.D.

Postdoctoral Fellows:  Julie Claycomb, Ph.D., Shenghua Duan, Ph.D., Weifeng Gu, Ph.D., Takao Ishidate, Ph.D., Ji Liu, Ph.D., Christopher Trzepacz, Ph.D., Hsin-Yue Tsai, Ph.D., Elaine Youngman, Ph.D.

Graduate Students:  Pedro Batista, Wei Cheng, Daniel Chaves, Soyoung Kim, Jessica Vasale

Academic Background

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.

Office: Biotech Two, Suite 219
Phone: 508-856-1602
E-mail: Craig.Mello@umassmed.edu
Keywords: RNA Interference (RNAi), Signal Transduction, Gene Expression, Developmental Biology

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Postdoctoral Position Available A postdoctoral position is available to study in this laboratory. Contact Dr. Mello for additional details.