Cell and Developmental Biology University of Michigan

Research

Hematopoietic stem cells, T cell differentiation and homeostasis, Notch signaling

Our research is devoted to the following main topics: 1) Understanding the role of Notch signaling in the regulation of T cell homeostasis and differentiation, particularly in the setting of allogeneic T cell responses; 2) investigating the homeostasis of blood-forming stem cells in situations of hematopoietic stress and the role of epigenetic regulation in their regulation.

In a first project, we are interested in the regulation of mature T cell homeostasis and differentiation by Notch signaling. Using several genetic models of Notch inactivation, we are investigating the molecular and cellular mechanisms underlying the activity of Notch signaling in allogeneic T cell responses (T cell responses against foreign tissue antigens). Our findings indicate that Notch behaves as a novel and potent master regulator of T cell function in several mouse models of graft-versus-host disease. We are currently investigating the molecular mechanisms of this effect and exploring its potential therapeutic applications.

In a second project, the Maillard laboratory is investigating the role of menin, a protein encoded by the Men1 tumor suppressor gene, in the regulation of hematopoietic stem cell homeostasis. Menin is a nuclear protein that functions as a cofactor for the Mixed Lineage Leukemia (Mll) gene product, a mammalian homologue of Drosophila Trithorax proteins that acts as a Histone 3 Lysine 4 (H3K4) methyltransferase in the epigenetic regulation of transcription. We have recently shown that menin is largely dispensable to support hematopoiesis in steady-state conditions, but becomes absolutely essential for hematopoietic stem cell function in situations of hematopoietic stress, such as after bone marrow transplantation. We are currently looking at the effect of menin loss on cell cycle regulation, survival and differentiation in hematopoietic stem cells. We are also investigating the interaction of other histone methyltransferases with menin and MLL. Finally, in collaboration with Dr. Catherine Keegan (Pediatrics), we are exploring the function of the “shelterin” complex in blood-forming stem cells.

Lab Members

• Julien Schira
  Research Fellow
• Ann Friedman
  Research Lab Specialist
• Morgan Jones
  Graduate Student
• Ashley Sandy
  Graduate Student
• Gloria Shan
  Undergradate Student
• Ivy Tran
  Research Lab Specialist

Publications

Representative Publications

1. Sandy AR, Maillard I. Notch signaling in the hematopoietic system. Expert Opin Biol Ther, 2009 Oct;9(11):1383-1398.
2. Maillard I, Chen YC, Friedman A, et al. Menin regulates the function of hematopoietic stem cells and lymphoid progenitors. Blood, 113(8): 1661-1669, 2009.
3. Maillard I, Koch U, Dumortier A, Shestova O, Xu L, Sai H, Pross SE, Aster JC, Bhandoola A, Radtke F, Pear WS. Canonical Notch signaling is dispensable for the maintenance of adult hematopoietic stem cells. Cell Stem Cell, 2(4):356-366, 2008.
4. Wu L*, Maillard I*, Nakamura M, Pear WS, Griffin JD. The transcriptional co-activator Maml1 is required for Notch2-mediated marginal zone B cell development. Blood, 110(10):3618-3623, 2007 (*equal contribution).
5. I. Maillard and W.S. Pear. Keeping a tight leash on Notch. Science, 316:840-842, 2007.
6. L. Talebian, Z. Li, Y. Guo, J. Gaudet, M.E. Speck, D. Sugiyama, P. Kaur, W.S. Pear, I. Maillard* and N.A. Speck*. T lymphoid, megacaryocyte, and granulocyte development are sensitive to decreases in CBFbeta dosage. Blood (Plenary paper), 109(1):11-21, 2007 (*corresponding authors).
7. Maillard I., L. Tu, A. Sambandam, Y. Yashiro-Ohtani, J. Millholland, K. Keeshan, O. Shestova, L. Xu, A. Bhandoola and W.S. Pear. The requirement for Notch signaling at the beta selection checkpoint in vivo is absolute and independent of the pre-T cell receptor. J. Exp. Med., 203(10): 2239-45, 2006.
8. Maillard I., B. Schwarz, A. Sambandam, T.Fang, O. Shestova, L. Xu, A. Bhandoola and W.S. Pear. Notch-dependent T lineage commitment occurs at extrathymic sites following bone marrow transplantation. Blood, 107(9): 3511-19, 2006.
9. Tu L., T.C. Fang, D. Artis, O. Shestova, S.E. Pross, I. Maillard and W.S. Pear. Notch signaling is an important regulator of type 2 immunity. J. Exp. Med., 202(8):1037-42, 2005.
10. Maillard I., T. Fang and W.S. Pear. Regulation of lymphoid development, differentiation and function by the Notch pathway. Annu Rev Immunol, 23:945-974, 2005.
11. Sambandam A.*, I. Maillard*, V.P. Zediak, L. Xu, R.M. Gerstein, J.C. Aster, W.S. Pear and A. Bhandoola. Notch signaling controls the generation and differentiation of early T lineage progenitors. Nature Immunology, 6(7):663-70, 2005 (*equal contribution).
12. Maillard I., A.P. Weng, A.C. Carpenter, C.G. Rodriguez, H. Sai, L. Xu, D. Allman, J.C. Aster, and W.S. Pear. Mastermind critically regulates Notch-mediated lymphoid cell fate decisions. Blood, 104(6):1696-702, 2004.