Harvard Medical School
Warren Alpert Bldg., Rm. 154
200 Longwood Ave.
Boston, MA 02115
The Rajewsky lab has explored how B lymphocytes develop from stem cells in the bone marrow of the mouse into mature cells and ultimately, upon contact with antigen, into memory cells. They have found that both the development and the maintenance of B cells depend on antigen receptor (BCR) expression, and they have explored the means by which B cells can somatically change BCR specificity and to which extent BCR specificity dictates the fate of the cells. In addition to a survival signal from the BCR, signals through other surface receptors are required to keep B cells alive in vivo. The nature and interplay of signals that control the homeostasis of both B and T lymphocytes in the living organism are a major focus of their research.
The main experimental approach has been gene targeting in embryonic stem (ES) cells of the mouse. Combining classical gene targeting techniques with Cre/loxP mediated site-specific recombination, the Rajewsky Lab has developed a method of targeted mutagenesis allowing the introduction of any kind of mutation into the mouse genome. This includes gene replacement and conditional gene targeting, i.e. targeted mutagenesis in a cell type specific and/or inducible manner.
Conditional gene targeting is ideally suited for the modeling of human diseases in mice. The group has produced numerous such mouse models, including models of various immunodeficiencies, Crohn's disease, and pulmonary fibrosis. Targeted mutagenesis of the NFkB signaling pathway has led to a mouse model of the genetic disease Incontinentia Pigmenti. Relating to this extensive earlier work on the origin of human lymphomas, in particular Hodgkin's disease (HD), they are presently heavily involved in generating mouse models of human mature B cell lymphomas.
More recently, the group has begun to explore the role of microRNA control in the immune system, using gene targeting, bioinformatic and proteomic approaches. This work has revealed a critical role of microRNAs in immune development and function, and microRNA control is now a major focus of the lab.
Srinivasan L, Sasaki Y, Calado DP, Zhang B, Paik JH, DePinho RA, Kutok JL, Kearney JF, Otipoby KL, Rajewsky K. PI3 kinase signals BCR-dependent mature B cell survival. Cell. 2009 Oct 30;139(3):573-86.
Derudder E, Cadera EJ, Vahl JC, Wang J, Fox CJ, Zha S, van Loo G, Pasparakis M, Schlissel MS, Schmidt-Supprian M, Rajewsky K. Development of immunoglobulin lambda-chain-positive B cells, but not editing of immunoglobulin kappa-chain, depends on NF-kappaB signals. Nat Immunol. 2009 Jun;10(6):647-54.
Otipoby KL, Sasaki Y, Schmidt-Supprian M, Patke A, Gareus R, Pasparakis M, Tarakhovsky A, Rajewsky K. BAFF activates Akt and Erk through BAFF-R in an IKK1-dependent manner in primary mouse B cells. Proc Natl Acad Sci U S A. 2008 Aug 26;105(34):12435-8.
Koralov SB, Muljo SA, Galler GR, Krek A, Chakraborty T, Kanellopoulou C, Jensen K, Cobb BS, Merkenschlager M, Rajewsky N, Rajewsky K. Dicer ablation affects antibody diversity and cell survival in the B lymphocyte lineage. Cell. 2008 Mar 7;132(5):860-74.
Xiao C, Calado DP, Galler G, Thai TH, Patterson HC, Wang J, Rajewsky N, Bender TP, Rajewsky K. MiR-150 controls B cell differentiation by targeting the transcription factor c-Myb. Cell. 2007 Oct 5;131(1):146-59.