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DURHAM, N.C. -- Neurobiologists have gained new insights
into how neurons control growth of the intricate tracery of
branches called dendrites that enable them to connect with
their neighbors. Dendritic connections are the basic receiving
stations by which neurons form the signaling networks that
constitute the brain's circuitry.

Such basic insights into neuronal growth will help
researchers better understand brain development in children, as
well as aid efforts to restore neuronal connections lost to
injury, stroke or neurodegenerative disease, said the
researchers.

In a paper published in the Dec. 8, 2005, issue of Neuron,
Howard Hughes Medical Institute investigator Michael Ehlers and
his colleagues reported that structures called "Golgi outposts"
play a central role as distribution points for proteins that
form the building blocks of the growing dendrites.

Besides Ehlers, who is at Duke University Medical Center,
other co-authors were April Horton in Ehlers' laboratory;
Richard Weinberg of the University of North Carolina at Chapel
Hill.; Bence Rácz in Weinberg's laboratory; and Eric Monson and
Anna Lin of Duke's Department of Physics. The research was
sponsored by The National Institutes of Health.

The Golgi apparatus is a cellular warehouse responsible for
receiving, sorting and shipping cargoes of newly synthesized
molecules needed for cell growth and function. Until the new
findings, researchers believed that only a central Golgi
apparatus played a role in such distribution, said Ehlers.

"In most mammalian cells, the Golgi has a very stereotyped
structure, a stacked system that resides near the cell nucleus
in the middle of the cell," he said. "But mammalian neurons in
the brain are huge, with a surface area about ten thousand
times that of the average cell. So, it was an entirely open
question where all the membrane components came from to
generate the complex surface of growing dendrites. And we
thought these remote structures we had discovered in dendrites
called Golgi outposts might play a role."

The researchers studied the dendritic growth process in
pyramidal neurons, which grow a single long "apical" dendrite
and many shorter ones. To explore the role of Golgi outposts,
they used imaging of living rat brain cells grown in culture,
as well as electron microscopy of rat brain tissue.

These studies revealed that the Golgi outposts tended to
appear in longer dendrites and also that those Golgi in the
main cell body tended to orient toward longer dendrites. And
importantly, said Ehlers, the studies in cell culture revealed
that the Golgi orientation preceded the preferential growth of
long dendrites.

"This finding showed us that we weren't just seeing a
correlation between Golgi and longer dendrites," said Ehlers.
"Initially, when these growing dendrites are all essentially
uniform in length, they grow at about the same rate. But later,
after the Golgi orient toward one dendrite, it takes off and
grows dynamically to become the longest dendrite." The
researchers also used tracer molecules to track the molecular
cargo secreted by the Golgi, said Ehlers.

"We saw very clearly that this cargo that originates in the
Golgi gets directed towards the one longest dendrite in a
highly preferential way," he said. "As cargo comes out of the
Golgi, it does not go randomly to the cell surface." Ehlers and
his colleagues also found that the Golgi outposts appeared to
locate themselves at dendritic branch points.

"This finding is important because a fundamental problem
that neurons must solve is how to sort appropriate cargo
molecules in the right amounts down different dendritic
branches," said Ehlers. "After all, different dendritic
branches can have different functional properties, molecular
composition and electrical properties. So, when a cargo reaches
a branch point, it's like a highway intersection, and the cargo
needs to be directed. We've found that these dendritic Golgi
outposts are located at the strategic points to do just that.
And I believe this is the first such specific organelle
identified at a dendritic branch point positioned to perform
this fundamental neuronal function."

Finally, the researchers disrupted the orientation, or
"polarity," of the Golgi -- thus causing them to move into all
the dendrites -- without disrupting their function. They found
that disrupting the polarity caused all the dendrites to grow
at the same rate.

Further studies, said Ehlers, will explore how Golgi
outposts arise, how they arrive at dendritic branch points and
what cargo they distribute. The researchers also will seek to
understand how molecules are selected for import to the distant
reaches of the dendrites and which will be locally synthesized
in the dendrites. Such studies could give important insights
into the machinery of neuronal growth and how it is controlled,
he said.

"Understanding this machinery has clinical relevance because
many disorders of brain development in children manifest
abnormal dendritic structures," said Ehlers. "Also, it turns
out that most neurodegenerative diseases, such as Parkinson's
and Alzheimer's, are disorders of protein processing. But we
know very little about how and where integral membrane proteins
are synthesized and processed by neurons."