A number of reports have recently described an unexpected degree of plasticity of stem cells derived from adult animals. These studies showed, for example, that transplantation of hematopoietic cells into irradiated mice leads to their transdifferentiation into muscle, liver and neural cells. However, whether similar processes occur in undisturbed animals remains unclear. This can now be studied with a technique that we recently developed and that allows to trace lineage ancestry in vivo. The technique is based on double transgenic mice in which expression of a lineage specific marker gene is translated into an irreversible DNA change that can be detected by LacZ expression. Using mice in which cells are tagged that express the lysozyme M gene (a myelomonocytic marker), as well as cells that once expressed the marker, we found that myelomonocytic cells are continuously reprogrammed into a subset of functional B lymphocytes. In addition, we discovered that brains of these mice contain a substantial proportion of cells derived from lysozyme expressors. Exploiting the Lysozyme-R-LacZ mouse model, we now propose to find out what the cells are that switch, into what types of brain cells they convert and how this happens during development. We will also use a more general approach to determine the spectrum of tissues in the body into which hematopoietic cells become reprogrammed normally, using mice expressing the pan-hematopoietic marker gene Vav.

Agency
National Institute of Health (NIH)
Institute
National Institute of Neurological Disorders and Stroke (NINDS)
Type
Research Project (R01)
Project #
5R01NS043881-04
Application #
6785848
Study Section
Special Emphasis Panel (ZHL1-CSR-J (S4))
Program Officer
Owens, David F
Project Start
2001-09-30
Project End
2006-07-31
Budget Start
2004-08-01
Budget End
2006-07-31
Support Year
4
Fiscal Year
2004
Total Cost
$374,410
Indirect Cost
Name
Albert Einstein College of Medicine
Department
Anatomy/Cell Biology
Type
Schools of Medicine
DUNS #
110521739
City
Bronx
State
NY
Country
United States
Zip Code
10461
Ye, Min; Graf, Thomas (2007) Early decisions in lymphoid development. Curr Opin Immunol 19:123-8
Stadtfeld, Matthias; Ye, Min; Graf, Thomas (2007) Identification of interventricular septum precursor cells in the mouse embryo. Dev Biol 302:195-207
Laiosa, Catherine V; Stadtfeld, Matthias; Graf, Thomas (2006) Determinants of lymphoid-myeloid lineage diversification. Annu Rev Immunol 24:705-38
Stadtfeld, Matthias; Graf, Thomas (2005) Assessing the role of hematopoietic plasticity for endothelial and hepatocyte development by non-invasive lineage tracing. Development 132:203-13
Ye, Min; Ermakova, Olga; Graf, Thomas (2005) PU.1 is not strictly required for B cell development and its absence induces a B-2 to B-1 cell switch. J Exp Med 202:1411-22
Xie, Huafeng; Ye, Min; Feng, Ru et al. (2004) Stepwise reprogramming of B cells into macrophages. Cell 117:663-76
Ye, Min; Iwasaki, Hiromi; Laiosa, Catherine V et al. (2003) Hematopoietic stem cells expressing the myeloid lysozyme gene retain long-term, multilineage repopulation potential. Immunity 19:689-99