December 12, 2005 —
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.
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
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.
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.
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."
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."
Source : Duke University Medical Center