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| Monterotondo, 3 September 2006 |
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| Lost in the labyrinth
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| Peggy Kirstetter and Claus Nerlov of EMBL Monterotondo |
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Decoding the instructions that tell cells how to become blood
Press
Release 3 September 2006 [PDF]
Blood cells have limited
lifespans, which means that they must be continually replaced by
calling up reserves and turning these into the blood cell types
needed by the body. Claus Nerlov and his colleagues at the
European Molecular Biology Laboratory [EMBL] unit in
Monterotondo, Italy, in collaboration with researchers from Sten
Eirik Jacobsen's laboratory at the University of Lund in Sweden,
have now uncovered how an intracellular communication pathway
contributes to this process. Because defects in such pathways
and in the development of stem cells frequently lead to leukemia
and other diseases, the work should give researchers a new handle
on processes within cells that lead to cancer. The work is published
in this week's online issue of Nature Immunology.
Over the past decades, molecular biologists have identified several
pathways – sequences of molecules which manage the flow of
information within the cell – responsible for major biological
processes. One of these, the 'Wingless' pathway, plays a vital role
in shaping tissues and organs in developing embryos of nearly all
animal species. It also helps organisms manage stem cells, by
keeping them on hold and preventing their differentiation until
the right time. Such pathways are usually switched on and off by
external stimuli that help cells respond properly to the environment.
Now Peggy Kirstetter and other members of Nerlov's lab
have shown what happens when Wingless is too active in
hematopoietic stem cells in mice.
"We modified one element of the pathway, a protein called 'beta-catenin',
so that it was stuck in 'transmission mode'," Kirstetter
says. "This created cells in which the pathway was always
switched on. We've known that Wingless contributes to blood differentiation,
but didn't know how the signals were being transmitted
within the hematopoietic stem cell."
The modified protein had dramatic effects. Usually, most cells
undergo numerous transitional stages on their way from stem
cells to fully-developed types in the blood. Several types of blood
cells vanished entirely; the same thing happened to more basic
cell types higher up in the blood lineage hierarchy. Particular
kinds of stem cells disappeared from the bone marrow of the
mice. Others were too frequent. Bone marrow cells didn't develop
into myeloid and red blood cells. B- and T-cells were also
blocked at early stages, but in a different way. This hints that they
may be controlled by other protein links in the Wingless pathway
as well. Perhaps most strikingly, beta-catenin appears to make
cells take decisions about their fate before they leave the stem cell
compartment in the bone marrow, something so far not thought
to occur.
The study proves that beta-catenin plays a central role in determining
whether blood cells form or not. On the other hand, an
overactive Wingless pathway doesn't seem to damage cells that
already exist. Thus beta-catenin seems to be a decision-maker, a
selector of how information gets routed within the cell, rather
than something which maintains the vitality of existing cells.
Nerlov compares the breakdown to people standing at a fork in a
labyrinth, hesitating before they go on. "We know there are
strong connections to cells' decisions to divide, to develop or to
die. If cells don't commit themselves to the right developmental
path at the right time, they're very likely to die or to begin an
inappropriate type of reproduction. Acute leukemias and other
forms of cancer cells derive from defects such as this.
Understanding the processes by which they form will require pinpointing
the forks in the road where things go wrong."
Source Article
P. Kirstetter, K. Anderson, B.T. Porse, S.E.W. Jacobsen & C. Nerlov. Activation of the canonical Wnt pathway leads to loss of
hematopoietic stem cell repopulation and multilineage differentiation block. Nature Immunology, 3 September 2006
Press Contact
Anna-Lynn Wegener
Press Officer
EMBL Heidelberg
Tel: +49 +6221 387-8452
Email: wegener@embl.de |
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