This image shows nerves (labeled in green) that control body movements emerging from the spinal cord of a mouse (upper left, in cross section) and connecting to muscles in the base of the leg. The Salk researchers discovered that a combination of genes direct nerves to split in the leg (lower right) to make the proper connections with their target muscles during early development. Credit: Image: Courtesy Dario Bonanomi, Salk Institute for Biological Studies |
Researchers
at the Salk Institute have discovered a startling feature of early
brain development that helps to explain how complex neuron wiring
patterns are programmed using just a handful of critical genes. The
findings, published February 3 in Cell,
may help scientists develop new therapies for neurological disorders,
such as amyotrophic lateral sclerosis (ALS), and provide insight into
certain cancers.
The
Salk researchers discovered that only a few proteins on the leading
edge of a motor neuron’s axon—its outgoing electrical “wire”—and within
the extracellular soup it travels through guide the nerve as it emerges
from the spinal cord. These molecules can attract or repel the axon,
depending on the long and winding path it must take to finally connect
with its target muscle.
“The
budding neuron has to detect the local environment it is growing
through and decide where it is, and whether to grow straight, move to
the left or right, or stop,” says the study’s senior investigator, Sam
Pfaff, a professor in Salk’s Gene Expression Laboratory and a Howard
Hughes Medical Institute investigator.
“It
does this by mixing and matching just a handful of protein products to
create complexes that tell a growing neuron which way to go, in the same
way that a car uses the GPS signals it receives to guide it through an
unfamiliar city,” he says.
The
brain contains millions of times the number of neuron connections than
the number of genes found in the DNA of brain cells. This is one of the
first studies to try and understand how a growing neuron integrates many
different pieces of information in order to navigate to its eventual
target and make a functional connection.
“We
focused on motor neurons that control muscle movements, but the same
kind of thing is going on throughout embryonic development of the entire
nervous system, during which millions of axons make trillions of
decisions as they move to their targets,” he says. “It is the exquisite
specificity with which they grow that underlies the basic architecture
and proper function of the nervous system.”
These
findings might eventually shed new light on a number of clinical
disorders related to faulty nerve cell functioning, such as ALS, which
is also known as Lou Gehrig’s disease, says the first author on the
paper, Dario Bonanomi, a post-doctoral researcher in Pfaff’s laboratory.
“These
are the motor neurons that die in diseases like Lou Gehrig’s disease
and that are linked to a genetic disorder in children known as spinal
muscle atrophy,” Bonanomi says.
“It
is also a jumping off point to try and understand the basis for defects
that might arise during fetal development of the nervous system,” he
added. “A better understanding of those signals might help to be able to
regenerate and rewire circuits following diseases or injuries of the
nervous system.”
The
researchers say the study also offers insights into cancer development,
because a protein the researchers found to be crucial to the “push and
pull” signaling system – Ret- is also linked to cancer. Mutations that
activate Ret are linked to a number of different kinds of tumors.
The other protein receptors described in the study, known as Ephs, have also been implicated in cancer, Pfaff says.
“This
study suggests that the way cells detect signals in their environment
is likely a universal strategy,” he says, “and we know that genes and
proteins known to function primarily during embryonic development have
been linked to cancer.”
“Controlling
neuronal growth requires very potent signaling molecules, and it makes
sense they would be linked to disease,” Pfaff says. “We hope our
findings help further unravel these connections.”
The study was funded by the National Institute of Neurological Disorders and Stroke and by the Howard Hughes Medical Institute.
Co-authors
include, from Salk, Onanong Chivatakar, Ge Bai, and Karen Lettieri;
Houari Abdesselem and Brian A. Pierchala, from the University of
Michigan School of Dentistry; and Till Marquardt, from the European
Neuroscience Institute-Göttingen, in Germany.
Ret Is a Multifunctional Coreceptor that Integrates Diffusible- and Contact-Axon Guidance Signals
