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Cabin1’s Regulation of MEF2 in the Developing Central Nervous System
Greenfield SMART Team: Robert Bhatia, Ellen Campbell, Chelsea Herr, Leticia Gonzalez, Alohani Maya, Danielle Murphy, Tiann Nelson-Luck, Kara Stuiber, and Jordan Tian
Teachers: Julie Fangmann and Martin Volk
1. Abstract
Cabin1 (calcineurin binding protein) is predicted to play an important role
in maintaining the nervous system, which regulates important functions
such as breathing, heart rate, thinking, and movement. Mice lacking Cabin1
die early in development, and other Cabin1 malfunctions have been linked
to cancer. As the nervous system develops, neurons require guidance to
determine their growth. The expression of specific proteins influences this
neuronal growth. Transcription factors, proteins that bind to DNA and
other proteins, regulate the production of these neuronal growth proteins.
MEF2 (myocyte enhancer factor 2), a protein known to bind to Cabin1, is
involved in nervous system development. MEF2 is a transcription factor
necessary for neuronal growth and survival. MEF2 activates transcription
when it binds to DNA, causing proteins involved in neural development to
be made. MEF2 has a hydrophobic binding pocket that attracts four amino
acids found on Cabin1: Ile106, Thre110, Ile116, and Leu119. When Cabin1,
a transcription repressor found in the nucleus, binds to MEF2’s
hydrophobic binding pocket, transcription is turned off. This prevents the
proteins from being produced and causes neurons to stop growing or to
potentially die. Since cell death and survival are both necessary for nervous
system development, Cabin1 is hypothesized to play a major role in this
process. Current research is examining what happens to neuronal growth
and survival when there is a shortage or an excess of Cabin1, eventually
leading to a better understanding of the precise way Cabin1 functions.
2. Introduction
Proper central nervous system (CNS) function depends on precisely
regulated gene expression during development. This maintenance of the
nervous system relies on two important proteins: Cabin1 and MEF2.
MEF2 is a transcription factor involved in the production of proteins
needed for neurons to grow and make connections. When Cabin1 binds to
MEF2 inside a neuron, protein production is prevented, potentially killing
off these cells. This is actually a good thing because cell death, as well as
cell survival, is necessary for nervous system development. Brain
development can be impaired if there are too few or too many neurons.
Mentor: Dena Hammond and Ava Udvadia, Ph.D., University of Wisconsin – Milwaukee
3. Nerve Cell Growth and Migration
The CNS is made up of the brain and spinal cord. Within the
cerebellum of the brain, granule cells are one major cell type .
During development, the granule cells proliferate in the external
granule layer (EGL) and migrate to the inner granule later (IGL),
where they make connections with other neurons. More cells are
made than are needed, so extra cells eventually die off. Cabin1 is a
protein that regulates which cells survive through its regulation of
protein synthesis.
Lai et al., 1998
Cabin1 is found in the adult (rat)
brain, especially in the cerebellum,
a site that produces new neurons.
Diaz lab
As the cerebellum develops, new
neurons form, move, and make
contact with other neurons.
4. Protein Synthesis
DNA contains genes that have the instructions to make
proteins. This process involves two majors steps: transcription
and translation.
Transcription is the process of
making mRNA, a copy of a gene.
This requires a number of
specific proteins, including
transcription factors.
Translation is the process of
using the instructions in the
mRNA to produce proteins.
Ribosomes bind to the mRNA
and help recruit the appropriate
building blocks used to make the
protein.
6. Cabin1 and MEF2
Cabin1, a transcription repressor (a protein) found in the nucleus, binds to
MEF2 to stop transcription. When Cabin1 binds and represses MEF2, proteins
needed for nervous system development are not produced, causing neurons
to die. This cell death during development is normal and necessary. If
Cabin1 is not functioning properly, too many nonfunctional neurons take
MEF2
up limited brain space.
part of
Cabin1
MEF2’s
Cabin1’s hydrophobic
DNA
binding
amino acids
pocket
attracted to
MEF2’s
binding
1n6j.pdb
pocket
MEF2 (blue and green subunits on the right) contains a hydrophobic binding pocket
(orange) which attracts four amino acids on Cabin1 (yellow on the left): Ile106,
Thre110, Ilel161, and Leu119 (all four are light blue on the left).
7. Current Research
It has been hypothesized that Cabin1 is involved in the proliferation and cell death
phase of nervous system development. Research about Cabin1 and nervous
system development is being conducted using zebrafish (below). Researchers have
linked a gene for GFP (a green fluorescent protein) to the gene for Cabin1 so
zebrafish cells will glow under UV light when they produce Cabin1. These glowing
cells are analyzed to determine the effects of knocking out the gene for Cabin1.
Control
A
B
Mutant
Severely
reduced brain
Brain
5. Transcription Factors and MEF2
MEF2 is a transcription factor made of two subunits (green and
blue below). Transcription factors are proteins that permit the
production of mRNA, leading to the production of other proteins
through translation.
Eye
Eye
Swelling
(edema) around
the heart
Heart
(Hammond and Udvadia, unpublished data)
Zebrafish lacking Cabin1 overproduce cell survival proteins in cells that should
normally die. This causes many mutations in an organism, as shown in Figure B.
Most of these animals die within 5 days after fertilization due to these mutations.
When Cabin1 binds to MEF2, transcription is inhibited. This action
helps regulate central nervous system functioning.
Image Sources:
http://www.ucdmc.ucdavis.edu/pharmacology/departmentlabs/diazlab.html
http://wofford-ecs.org/DataAndVisualization/GenomicData/images/mrna.gif
Udvadia lab at the UW-Milwaukee Water Institute
A SMART Team project supported by the National Institutes of Health (NIH)-National Center for
Research Resources Science Education Partnership Award (NCCR-SEPA).
8. Future Research
MEF2 activates transcription when it binds to DNA. MEF2 is
important in gene expression and protein production dealing
with nervous system development because it helps keep
useful cells alive.
•Further research will determine what a lack of Cabin1 will cause. This new
information, could help determine the exact role of Cabin1 in programmed nerve
cell death.
•Some research has found a potential link between a lack of Cabin1 and cancer.,
possibly due to an over-expression of proteins. As more is learned about Cabin1,
these and other mysteries might be cleared up.