Defying Death: Neuron survival strategies differ between embryonic and adult mice (Neurodegenerative disease)
Authors: Seydel Caroline 
Published: August 2003

By generating new nerve cells, researchers hope that they can reverse the damage caused by neurodegenerative diseases. For inspiration, they typically turn to embryos, which sculpt entire organ systems out of raw cellular materials. By duplicating embryonic strategies, the theory goes, we can create new neurons at will. But what if tactics used by the embryo don't always work in adult tissue? Previous findings suggest that they might not, and now researchers have new evidence that a key protein governing recovery from injury in adult mice might be dispensable in the developing embryo.

Ordinarily, about 20,000 motor neurons develop in the spinal cord of an embryonic mouse, but naturally occurring cell death culls about half of them before birth. Those that survive do so with the help of growth factors, including at least one family that activates a signaling pathway that turns on a gene called
Stat3
. Getting rid of
Stat3
should result in mice with fewer motor neurons, the researchers reasoned. To test this idea, Schweizer and colleagues created a strain of mice whose
Stat3
gene was disabled in motor neurons and compared them to siblings with operational
Stat3
.

Contrary to the team's prediction, mice didn't appear to miss
Stat3
much during embryonic development: At birth, animals without the gene retain the same number of motor neurons as those that carry
Stat3
. After birth, however, mice need it to prevent the cell death that results from injury. When the researchers severed the facial nerve of 4-week-old mice, cutting off the supply of growth factors to the facial motor neurons, nearly half of those motor neurons died in mice that lacked
Stat3
. Mice whose motor neurons produced
Stat3
, however, lost few nerve cells. These results support the notion that different mechanisms might govern cell death in developing embryos and in adult injuries.

In another experiment, the team applied a growth factor called CNTF to the cut facial nerve of mice without
Stat3
. The growth factor enabled the mice to retain about half the motor neurons that would otherwise have died--a surprising result, considering that CNTF works through
Stat3
. Somehow CNTF helped the neurons survive even without
Stat3
, indicating that it can act through signaling pathways that don't employ
Stat3
; the researchers hope to uncover those pathways soon.

By finding that loss of
Stat3
prevents injured neurons from recovering but doesn't interfere with neuron survival during embryonic development, the research supports earlier observations that CNTF and related growth factors act primarily in injury repair rather than in embryonic development. The embryonic nervous system uses very little CNTF, for example. Studying and understanding the chemical ranks that shield the adult nervous system from damage could yield valuable therapeutic information, and further research will likely tease out which players take center stage at different points in an animal's life.

--Caroline Seydel

U. Schweizer, J. Gunnersen, C. Karch, S. Wiese, B. Holtmann, K. Takeda, S. Akira, M. Sendtner, Conditional gene ablation of Stat3 reveals differential signaling requirements for survival of motoneurons during development and after nerve injury in the adult.
J. Cell Biol.
156
, 287-299 (2002).
[Abstract]
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