(Philadelphia, PA) - Researchers at the University
of Pennsylvania School of Medicine have discovered that
nerve-cell dendrites have the capacity to splice messenger RNA (pre-mRNA),
a process once believed to only take place in the nucleus of cells.
By uncovering this capability in dendrites, the investigators hope
to relate this capacity to memory and learning, as well as cognitive
dysfunction. Senior author James Eberwine, PhD,
Professor of Pharmacology, and lead authors Kevin Miyashiro,
and Jason Glanzer, PhD, both in Eberwine’s
lab, report their findings in this week's early online edition of
the Proceedings of the National Academy of Sciences.
which branch from the cell body of the neuron, play a key role in
the communication between cells of the nervous system, allowing
for many neurons to connect with each other to form a network. Dendrites
detect the electrical and chemical signals transmitted to the neuron
by the axons of other neurons. The synapse is the neuronal structure
where this chemical connection is formed, and investigators surmise
that the synapse is where learning and memory occur.
Researchers have long agreed that mRNA splicing takes place within
the cell nucleus. In the nucleus of a mammalian cell, a gene is
copied into mRNA, which possesses both exons (mature mRNA regions
destined to code for proteins) and introns (non-coding regions).
mRNA splicing works by cutting out introns and merging together
the remaining exon pieces, resulting in an mRNA capable of being
translated into a specific protein.
The vast array of proteins within the human body arises in part
from the many ways that mRNAs can be spliced and reconnected. Specifically,
splicing removes pieces of intron and exon regions from the RNA,
with the resulting spliced RNA often being made into protein. Should
the RNA have different exons spliced in and out of it, then different
proteins can be made from this RNA. The Eberwine lab was successful
in showing that splicing can occur in dendrites because they have
employed very sensitive technologies developed in their lab, which
permits the detection and quantification of RNA splicing as well
as the translated protein in single isolated dendrites.
"In addition to showing that mRNA splicing occurs in dendrites
in which we added mRNA, we also detected the resulting protein,"
notes Eberwine. "Since the splicing machinery is present in
dendrites, one could speculate that if pre-mRNA is present naturally
in the dendrite, when activated, it may be spliced and translated,
giving rise to many different proteins."
Protein diversity is a key aspect to the complexity of the central
nervous system. Proteins are the workhorses of the cell and are
generally responsible for insuring that cells function properly.
When proteins interact with one another they can elicit specific
physiological responses, including the generation and maintenance
of memories. Changing protein identity, as can occur with splicing,
can change the ability of the protein to interact with other proteins
and therefore potentially change such physiological processes. With
the dendrite being the initial site in the neuron where learning
is thought to occur, the ability to create a diversity of mRNAs,
through local splicing, and subsequent protein translation may permit
exquisitely sensitive control of these cellular functions.
“The regulation and timing of the expression of proteins is
what makes the central nervous system function," says Eberwine.
The diversity and redundancy of the nervous-system proteins may
serve to help maintain the system over a lifetime. However, failure
in protein regulation or proper expression in neurons may give rise
to cognitive dysfunction. “Most neurodegenerative and psychiatric
illnesses exhibit dendrite dysfunction, therefore, the inability
to properly generate spliced RNAs in dendrites or proteins may underlie
aspects of these disease processes.”
By revealing the capacity of mRNA splicing in dendrites, the investigators
hope to develop an understanding of its role in cognition and dysfunction.
Eberwine and colleagues are now working to find an endogenous mRNA
that will undergo splicing within dendrites.
Co-authors in addition to Eberwine, Glanzer, and Miyashiro are Jai-Yoon
Sul, Lindy Barrett, Brian Belt, and Phillip Haydon, all from Penn.
This worked was funded by the National Institute on Aging and the
National Institute on Mental Health.
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