Wed Jul 30 13:40:17 2003 Pacific Time

      Stem Cell Death Gives Clue to Brain Cell Survival

       AUGUSTA, Ga., July 30 (AScribe Newswire) -- A signal that triggers half the stem cells in the developing brain
to commit suicide at a stage where their survival will likely do more harm than good has been identified by researchers
at the Medical College of Georgia and the University of Georgia.

       Identifying the factors that result in the timely, massive cell suicide is important to understanding the
developmental puzzle, the researchers say of the work featured on the cover of the Aug. 4 issue of the Journal of Cell
Biology.

       They say it also gives clues about cell death - and the brain's possible recovery - in devastating diseases such
as Alzheimer's, Parkinson's and stroke.

       MCG's Dr. Erhard Bieberich and UGA's Dr. Brian G. Condie have found that the lipid ceramide and the protein PAR-
4 - each already implicated for playing a role in cell death - become deadly partners inside a dividing stem cell in
the developing mouse brain.

       "If PAR-4 is there and ceramide is high, the cell is lost, doomed to die," says Dr. Bieberich, biochemist at the
Medical College of Georgia. "You can eliminate one of them, you can knock down the expression of PAR-4 or ceramide and
the other stays up but the cell doesn't die. But if both signals are together up-regulated, then the cell is destined
to die."

       At a certain point in cell division, just before neurons begin forming, there is massive production of proteins
and up-regulation of lipids. During that phase, decisions are made about which daughter cells get what composition of
lipids and proteins, decisions that affect the cells' future function.

       Typically at this point in division, the two daughter cells birthed from a single stem cell will have the same
makeup and the same ultimate purpose.

       Yet in a subpopulation of the stem cells involved in brain development, the scientists have documented
increasing levels of ceramide in both resulting daughter cells while its death partner, PAR-4, gets handed off to only
half the cells.

       Cells destined to survive, and likely further divide and differentiate, are handed instead a protein called
nestin. "Nestin is a marker for a particular stage of neuronal development," says Dr. Bieberich. "Nestin-bearing cells
will develop into neural cells such as our neurons or astrocytes or other cells. So it makes sense that the cells that
inherit nestin, but not PAR-4, will survive and develop into normal neuronal cells whereas the other ones will die."

       It also makes sense that the lethal coupling that signals cell suicide, or apoptosis, comes at a point where the
doomed cells seem to have lost their potential usefulness and where their continued survival would result in a
malformed brain.

       "During normal development in the central nervous system there is a great deal of cell death that occurs that
seems to be required to create the final shape and structure of the brain," says Dr. Condie, developmental
neurobiologist at the University of Georgia and MCG. "In cases where that process has been interfered with, you end up
with this excess of cells that leads to a malformation of the developing brain.

       "One of the ideas behind why there is an excess of cells generated during development is that it may be a
mechanism for compensating for environmental stresses or other types of stresses that an embryo may encounter during
development," says Dr. Condie. "So you actually generate an excess of the cells you need and then prune those cells
back to an appropriate number and location for the brain to develop in a normal fashion." It's a typical characteristic
of embryonic development for certain cells to survive and others to die, he says.

       "During embryonic development, we would like to know how stem cell death is regulated because we know it needs
to be regulated," says Dr. Bieberich. "You don't want the whole brain dying or overgrowing. You have to find a balance.
How is that balanced maintained? What are the secrets for that?

       "We have designed experiments showing that these two signals are necessary to make stem cells die, but you are
talking about a whole signaling cascade that starts out with ceramide and PAR-4 and then there are a lot of unknown
steps until we end up with the actual death of a cell," says Dr. Bieberich.

       The MCG researcher recently received a grant from the National Institutes of Health so he and Dr. Condie can
explore these unknowns such as how the expression of PAR-4 and ceramide is regulated, what accounts for the
asymmetrical distribution of PAR-4 and just how the deadly duo interact.

       But the two are excited about what they have found already. "If we don't know the signals, we don't know where
to begin," says Dr. Bieberich.

       They also are intrigued by where the work may lead, including helping minimize cell death that occurs when stem
cells in the adult brain begin to once again divide in response to a stroke, as an example.

       "We all know that even in adulthood, we have stem cells in the brain and they may be able to repair damaged
areas," says Dr. Bieberich. "But if the same cell death mechanisms are still active, there will not be an increase in
the number of stem cells because always one cell will die and one will survive. Maybe we can control this and increase
the number of endogenous stem cells.

       "Also during the neurodegeneration that occurs in diseases such as Alzheimer's and Parkinson's, we have a lot of
cell death going on and we would like to know what signals are involved that make those brain cells die. They may be
very similar or even exactly the same as the ones we investigate with our embryonic mouse stem cells."

       Study co-authors include Scott Noggle, an MCG graduate student working with Dr. Condie at UGA; Sarah MacKinnon,
a former participant in MCG's summer research programs for undergraduates who is now a graduate student at the
University of Virginia; and Dr. Jeane Silva, Dr. Bieberich's research coordinator.

       The Medical College of Georgia is the state's health sciences university and includes the Schools of Allied
Health Sciences, Dentistry, Graduate Studies, Medicine and Nursing, MCG Hospital and Clinics and the Children's Medical
Center.

      -30-

SOURCE: AScribe - The Public Interest Newswire
http://tinyurl.com/ilg6
http://www.ascribe.org/cgi-bin/spew4th.pl?ascribeid=20030730.121022&time=13%2040%20PDT&year=2003&public=1

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