Receptor Linked to Brain Development, May Play Role in Alzheimer’s
Defects in Astrocyte Formation Could Contribute to Disease
In its earliest moments, the developing brain is a formless array of precursor
cells, each facing an ultimate decision. Either become a -message-bearing
neuron or join the ranks of that broadly defined class of helper cells, the
glia. The majority will follow the latter course—glial cells are thought
to outnumber neurons by as much as 10 to one. Of these, most will become
star-shaped astrocytes. Yet precursor cells develop into glia only after
the neurons have started forming, which has led to speculation. Are the precursors
simply receiving their astrocyte-determining signal after the neurons receive
their direction? Or does the fate-determining message arrive promptly but
get repressed, perhaps by another signal?
Photo by Graham Ramsay
Astrocyte formation entails a novel and surprising pathway.
The findings by (clockwise from left) Gabriel Corfas, Samir Koirala, Joshua
Murtie, and S. Pablo Sardi could have implications for Alzheimer’s
and other neurodegenerative diseases.
The results of a four-year study suggest the latter may be the case. Gabriel
Corfas, S. Pablo Sardi, and colleagues report that a well-known messenger,
neuregulin, represses a growth factor known to stimulate astrocyte formation.
And it does so by setting in motion a lively sequence of events, beginning
with the activation of a quirky receptor protein, erbB4. Most receptors relay
messages by a phosphorylation cascade, but erbB4 can take a less conventional
route. Once activated, it breaks off just inside the membrane. The Corfas
team found that the cleaved bit teams up with at least two other proteins
and travels directly to the nucleus, where it turns off a key astrocyte-determining
This sequence appears to play out in mammals. Mice lacking the erbB4
gene produced astrocytes earlier in embryonic development than did controls.
Astrocyte development could be put back on course by introducing the cleaved
portion of erbB4. The findings appear in the Oct. 6 Cell.
What makes the scenario especially intriguing is that the protein responsible
for cleaving erbB4 is none other than presenilin, long implicated in Alzheimer’s
disease. “Alterations in presenilin activity cause Alzheimer’s
disease, but it is believed that this is primarily through the processing
of amyloid precursor protein,” said Corfas, HMS associate professor
of neurology at Children’s Hospital Boston. The new findings suggest
that defects in presenilin activity could also work through the processing
This is not the first time erbB4 has been linked to Alzheimer’s.
Plaques found in the brains of patients have already been shown to exhibit
an abundance of the protein. The new findings suggest that presenilin-mediated
defects in the processing of erbB4 could act early in a patient’s life. “This
study raises the possibility that there is a developmental contribution to
Alzheimer’s disease, that people who develop Alzheimer’s may
have some essential weakness in the brain that makes it more susceptible
to the accumulation of stress and insult during life, which can bring about
neurodegeneration,” Corfas said. “Perhaps alterations in types
or locations of astrocytes affect the susceptibility of neurons to insults.”
Receptor with Legs
Astrocytes do more than protect neurons. They regulate the ionic balance
in the extracellular environment, clean up excess neurotransmitters, induce
the formation of synapses, and make the blood–brain barrier. An imbalance
in the ratio of astrocytes to neurons, caused perhaps by defects in the erbB4 gene
itself, could be devastating not just in early development but throughout
life. Variations in the erbB4 gene have been linked to schizophrenia,
a disease characterized by an overgrowth of synaptic connections in certain
regions of the brain.
Illustration by Rachel Eastwood, based on original courtesy of S.
Twist of fate. Upon activation by neuregulin, erbB4
is cleaved extracellularly by TACE and intracellularly by presenilin. The
erbB4 intracellular domain, E4ICD, pairs with TAB2, which in turn binds N-CoR.
The trio travels to the nucleus and, with an unknown DNA-binding partner,
turns off key astrocyte-determining genes.
Corfas; Sardi, an HMS research fellow in neurology; and their colleagues
had no idea that erbB4 played a role in astrocyte differentiation back in
2002. What they did know, thanks in part to studies in the Corfas lab, is
that erbB4 was a peculiar protein with the strange habit of splitting and
translocating to the nucleus when activated. “That suggested that the
intracellular domain of the receptor could have new and different ways of
signaling, but it was not clear what, how, or where,” Corfas said.
on what would be an arduous quest, he and Sardi began looking for possible
partners of the erbB4 intracellular domain (E4ICD). Using a classic yeast
two-hybrid system, they netted several candidates, including TAB2. The protein
looked promising—it was known to shuttle between the cytoplasm
and nucleus, and it could bind to a known transcription repressor, N-CoR.
They decided to test the pair in cultured mammalian cells and found that
E4ICD did team up with TAB2, and that TAB2 bound N-CoR. The trio then moved
to the nucleus.
Yet it was still not clear where—in which cells—the
interaction was occurring. The researchers tested a variety of cells before
focusing on neural precursors. They then reran all the previous experiments.
The same erbB4–TAB2–N-CoR scenario played out in the neural precursor
cells. They wanted to find out what effect the activation and subsequent
translocation of erbB4 was having. “Generally when you activate a receptor
tyrosine kinase like erbB4, something happens—cells proliferate, they
die, they differentiate, they move,” said Corfas. He and Sardi exposed
the neural precursor cells to erbB4’s preferred ligand, neuregulin. “Nothing
happened,” he said. “It was a big disappointment.”
“This study raises the possibility that there is a developmental
contribution to Alzheimer’s disease, that people who develop
Alzheimer’s may have some essential weakness in the brain that
makes it more susceptible to the accumulation of stress and insult
that the situation might be more complex—that activation
of erbB4 by neuregulin might be affecting how the neural precursor cells
were responding to other signals—they exposed neural precursors to
platelet-derived growth factor (PDGF), which is known to stimulate neurons
to differentiate. They then added neuregulin. “Still nothing happened.
That was another depressing point,” said Corfas. It was only when they
added ciliary neurotrophic factor (CNTF), which promotes the differentiation
of astrocytes, that they began to see a repressive effect.
Three years into
their series of experiments, the researchers had pieced together a compelling
tale, but it was still not clear if erbB4 activation was repressing astrocyte
formation in living animals. It turns out, a viable erbB4-knockout mouse
had been generated. Corfas and colleagues found that the brains of the animals
exhibited precocious astrocyte development. Clearly erbB4 was important,
but the protein is also capable of signaling by conventional phosphorylation.
They wanted to show that erbB4 was carrying out its repressive effects by
breaking off and traveling to the nucleus. “To do that,
we had to do another series of tough experiments,” Sardi said.
with Joshua Murtie and Samir Koirala, HMS research fellows in neurology,
they introduced two different forms of erbB4, normal and noncleavable, into
the knockout embryos and waited to see which would be rescued. Only the cleavable
form of erbB4 was able to rescue the mice and put astrocyte differentiation
on a normal timetable. A final experiment showed that it does so single-handedly,
without any phosphorylation cascade.
It is still not clear how defects in
presenilin might affect the cleaving and translocation of erbB4. Making matters
more interesting, erbB4 is likely to interact with proteins other than TAB2
and N-CoR. “Most probably
this is quite a large complex, and we are working on identifying all the
components,” said Corfas.