Abstract

RNA intererence is a one of the major mechanisms of post-transcriptional regulation of protein expression in eukaryotes. This mechanism is using small non-coding RNAs (miRNAs) to destabilize specific mRNAs and to suppress protein synthesis. Many miRNAs genes are expressed in T cells during development in a thymus. However the function of RNAi in T cell development remains unclear. To investigate the role of RNAi during thymic development we generated conditional knockout of the enzyme Dicer in the mouse, which is critical for miRNA generation. We observed a dramatic reduction in the number of thymocytes in Dicer-deficient mice and we determined that the reason is a block of progression from DN to DP stage during thymocyte development. Importantly, we found an alteration in the balance between pro- and anti-apoptotic factors in RNAi deficient DP thymocytes. We also observed that RNAi-deficient thymocytes are rapidly undergoing apoptosis. Most importantly, we have also identified the precise gene whose expression is downregulated by microRNAs to permit survival of developing T cells in the thymus.

  Funding Agency

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Investigator-Initiated Intramural Research Projects (ZIA)
Project #
1ZIABC011114-06
Application #
8763352
Study Section
Project Start
Project End
Budget Start
Budget End
Support Year
6
Fiscal Year
2013
Total Cost
$244,735
Indirect Cost

  Institution

Name
National Cancer Institute Division of Basic Sciences
Department
Type
DUNS #
City
State
Country
Zip Code

  Publications

Pobezinsky, Leonid A; Etzensperger, Ruth; Jeurling, Susanna et al. (2015) Let-7 microRNAs target the lineage-specific transcription factor PLZF to regulate terminal NKT cell differentiation and effector function. Nat Immunol 16:517-24
Takada, Kensuke; Van Laethem, Francois; Xing, Yan et al. (2015) TCR affinity for thymoproteasome-dependent positively selecting peptides conditions antigen responsiveness in CD8(+) T cells. Nat Immunol 16:1069-76
Tai, Xuguang; Singer, Alfred (2014) Basis of Treg development in the thymus. Cell Cycle 13:501-2
Van Laethem, François; Tikhonova, Anastasia N; Pobezinsky, Leonid A et al. (2013) Lck availability during thymic selection determines the recognition specificity of the T cell repertoire. Cell 154:1326-41
Kimura, Motoko Y; Pobezinsky, Leonid A; Guinter, Terry I et al. (2013) IL-7 signaling must be intermittent, not continuous, during CD8? T cell homeostasis to promote cell survival instead of cell death. Nat Immunol 14:143-51
Tai, Xuguang; Erman, Batu; Alag, Amala et al. (2013) Foxp3 transcription factor is proapoptotic and lethal to developing regulatory T cells unless counterbalanced by cytokine survival signals. Immunity 38:1116-28
Pobezinsky, Leonid A; Angelov, Georgi S; Tai, Xuguang et al. (2012) Clonal deletion and the fate of autoreactive thymocytes that survive negative selection. Nat Immunol 13:569-78
McCaughtry, Tom M; Etzensperger, Ruth; Alag, Amala et al. (2012) Conditional deletion of cytokine receptor chains reveals that IL-7 and IL-15 specify CD8 cytotoxic lineage fate in the thymus. J Exp Med 209:2263-76
Tai, Xuguang; Van Laethem, Francois; Pobezinsky, Leonid et al. (2012) Basis of CTLA-4 function in regulatory and conventional CD4(+) T cells. Blood 119:5155-63
Adoro, Stanley; Park, Jung-Hyun; Singer, Alfred (2012) Coreceptor gene ""imprinting:"" a genetic solution to a developmental dilemma in T cells. Cell Cycle 11:833-4

Showing the most recent 10 out of 14 publications