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| Research
Group |
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| Research
Interests |
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My
group is interested in the molecular mechanisms maintaining stem cell
compartments in addition to the mechanisms driving non-committed precursor
cells into differentiation.
Homeostasis
of self-renewing systems such as the skin and the hematopoietic compartment
require maintenance of stem cells in addition to mechanisms driving these
cells into differentiation. Mechanisms underlying self-renewal and differentiation
are largely unknown.
Genes involved in regulating these events have been identified primarily
on the basis of genetic approaches. In developmental systems, lateral
cell contact mediated signaling involving members of the Notch receptor
gene family and corresponding ligands have been shown to modulate cell
fate decisions in pluripotent progenitors. The roles of Notch genes, their
ligands, and the downstream elements in signal transduction cascades have
been intensively investigated in Drosophila and exploration is starting
in the mouse. However, investigation of the role of Notch genes and their
ligand family members in mammalian cell fate specification is hampered
by the fact that gene inactivation results in early embryonic lethal phenotypes.
We
investigate the role of Notch receptor and ligand family members in the
hematopoietic system as well as in the skin by the means of conditional
gene targeting in the mouse. One particular goal is to compare the function
of these gene family members in epithelial (skin) versus non-epithelial
(hematopoietic) systems in respect to maintenance of stem cells or induction
of differentiation. Furthermore we are interested to understand how deregulation
of these gene family members is linked to tumorigenesis.
| Current Projects |
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Role
of Notch receptor and ligand family members in hematopoiesis. We have
recently used the Cre-loxP recombination system to generate mice in which
the Notch1 gene can be either conditionally inactivated in the bone marrow
or at different developmental stages of thymocyte development. Using this
system the Notch1 receptor was shown to be essential for T cell development,
and furthermore is involved in T/B cell fate determination. Inactivation
of Notch1 during intra-thymic T cell development beyond the pre TCR checkpoint
has no effect on subsequent T cell development, while its inactivation
before the pre-TCR chekpoint suggest a role for Notch1 signaling in VDJb-rearrangement.
Furthermore Notch1 signaling is involved in eliminating cells with defective
pre TCR.
We are currently working on the mechanism of action of the Notch1 receptor
and identification of downstream genes involved in early T versus B cell
fate specification. 2. Elucidation of mechanisms controlling compartimentalization
of B- and T cell development. 3.The role of Notch1 in VDJb-
rearrangement. 4.Identification and characterization of cells receiving
Notch signals. 5. The role of Notch1 during an immune response. 6.The
roles of other Notch receptors and their ligand family members during
hematopoiesis.
Notch
signaling in skin and hair follicle homeostasis. In addition to the
hematopoietic compartment, Notch receptors and ligand family members are
also expressed in self-renewing epithelial tissues such as such as the
mammalian skin and hair follicles. However, the role of Notch signaling
in hair follicle homeostasis and mammalian skin is not well understood.
In addition abberrant Notch signaling has been associated with an oncogenic
role in tumorigenesis.
We use the Cre-ERT-loxP system to study the physiological role of Notch
receptors and ligands in the murine hair follicle, epidermis and the corneal
epithelium of adult mice as well as its role in skin tumorigenesis. We
aim to uncover the molecular mechanisms by which Notch1 controls hair
cycle homeostasis and epidermal differentiation and proliferation by using
a combination of cellular, biochemical and tissue inducible gene targeting
approaches.
| Selected
publications |
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Rangarajan, A., Okuyama,
R., Talora, C., Nicolas, M., Krishna, S., Aster, J.C., Metzger, D., Chambon,
P., Miele, J., Aguet, M., Radtke F. and Dotto, G.P. 2001. Notch1 functions
as an essential determinant of keratinocyte exit from the cell cycle and
entry into differentiation. Embo J. 20:3427-3436.
Wilson, A., MacDonald,
H.R. and Radtke, F. 2001. Notch 1-deficient common lymphoid precursors
adopt a B cell fate in the thymus. J. Exp. Med. 194:1003-1012.
Wolfer, A., Bakker,
T., Wilson, A., Nicolas, M., Ioannidis, V., Littman, D.R., Peggy, P.L.,
Wilson, C.B., Held, W., MacDonald, H.R. and Radtke, F. 2001. Inactivation
of Notch1 in immature thymocytes does not perturb CD4 or CD8 T cell development.
Nat. Immunol. 2:235-241.
Radtke, F., Wilson,
A., Stark, G., Bauer, M., van Meerwijk, J., MacDonald, H.R. and Aguet,
M. 1999. Deficient T-cell fate specification in mice with an induced inactivation
of Notch1. Immunity 10:547-558.
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