September 09, 1998
Simple Chemical Switches Steer Migrating Neurons
In an embryo's developing brain and spinal cord, the growing ends of nerve cells, called axons, travel great distances to
make precise connections with other neurons. Without such accurate
connectivity, the nervous system would never wire properly.
An axon's path towards a target neuron is steered by growth cones that
are located in the tip of the axon. These growth cones receive cues
about the best path to follow from chemical attractants and repellents
secreted by cells in the central nervous system.
Until recently, scientists assumed that type of neuron and the unique
chemical receptors found on its surface determined whether a neuron is
attracted to or repelled by a given guidance chemical. Now, HHMI
investigator Marc Tessier-Lavigne at the University of California, San
Francisco, working with Mu-ming Poo and colleagues at the University of
California, San Diego (UCSD), has found that a single chemical cue can
either attract or repel, depending on the growth cone's internal status.
This research is reported in the September 4, 1998, issue of the journal
Science.
This work, says Tessier-Lavigne, may hold promise for regenerating
nerves damaged by spinal cord injury. It also provides potentially
important clues for understanding disorders of neuronal migration, which may be responsible for childhood epilepsy, forms of mental retardation, and possibly
dyslexia and schizophrenia.
The researchers found that two key signaling chemicals, cyclic AMP and
cyclic GMP, located in the growth cone, act as switches. In general,
increasing levels of these cyclic nucleotides promotes attraction, while
lowering levels favors repulsion. Thus, both attraction and repulsion
share a common chemical switch.
In studying spinal cord neurons cultured from frog embryos, the
investigators found evidence of two steering-related circuits within the
growth cones, one responding to cyclic AMP, the other to cyclic GMP. For
example, a repulsive signal-where growth cones turn away from the source
of the chemical cue-became attractive when cyclic GMP was added to the
growing neurons. In contrast, a different repulsive signal became
attractive when cyclic AMP was added to the growing neurons.
Several years ago, Tessier-Lavigne's group discovered netrin-1, a
chemical that attracts growth cones. In an article published in
Neuron
in December 1997, Tessier-Lavigne's and Poo's groups showed that netrin-1 can also repel
growth cones when cyclic AMP is lowered. Both the attraction and the
repulsion were abolished by lowering calcium levels. In the article
published in
Science,
the researchers show that calcium dependence
emerged as a consistent feature of cues influenced by the cyclic AMP
circuit.
"It's remarkable that all five cues we've looked at so far fit this
simple picture," said Tessier-Lavigne. "We seem to be tapping into some
primordial guidance mechanisms. The growth cone is a machine designed to
respond to the environment by turning one way or the other, so maybe
it's not so surprising there are only a limited number of ways of
accessing that machine."
That is not the end of the story, however. Cyclic AMP and cyclic GMP
levels are controlled by other factors in the growth cone's
ever-changing external environment. This, says Tessier-Lavigne, suggests
that "the response of a growth cone to a particular guidance cue may
depend critically on other signals received by the neuron. The
susceptibility to conversion between attraction and repulsion may enable
a growing axon to respond differentially to the same guidance cue at
different points along the journey to its final target."
In an accompanying commentary in the same issue of
Science,
Pico Caroni
of the Miescher Institute in Switzerland cites as "most exciting" the
possibility that damaged nerves might be regenerated by treating them with drugs that
boost the levels of these molecular cues, reversing the action of
repulsive factors.
For example, MAG, a component of a neuron's protective myelin sheath, is
known to actively block axonal regeneration. The researchers showed that
MAG, which is normally repellent, can become an attractant when cyclic
AMP levels are raised.
"Since many different inhibitory factors that prevent regeneration
likely act through these chemical cue systems, we have a better chance
of reversing all inhibitory actions by this type of manipulation," said
Poo. He also noted that experiments in live animals would follow,
and-assuming those studies are promising-eventually clinical trials in
humans.
In vivo
studies will be needed to test whether the switching mechanism
discovered in the cell culture model is actually being used by the
developing organism, added Tessier-Lavigne.
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