Biology concepts – undulipodia, primary cilia, chemosensing,
obesity, depression, hydrocephalus, lithium
Winston Churchill once said that men occasionally stumble on
the truth, but most people pick themselves up and carry on as if nothing had
happened.
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Gregor
Mendel was Augustinian monk who really
joined
the order because they would allow him to
study
and learn for the rest of his life. Sounds like
the
gig I would enjoy. Since he was a monk, do you
think
he got angry that his discoveries were
ignored
for 35 years?
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Mendel's paper was referenced only three times over next 35
years and his work wasn’t rediscovered until 1900. Two scientists gave Mendel
much credit for the primacy of his work, but it really wasn’t until a fourth
individual, William Bateson, came along that Mendel became widely known and his
work accepted. It was Bateson coined the phrase “Mendel’s laws of inheritance.”
Why did he champion Mendel so greatly – because he questioned Darwinism as
incomplete. Well, it was incomplete at that time.
Just as the world was rediscovering Mendel, the primary cilium was discovered for the first time. The world didn’t exactly ignore it; we
just had to wait for technology to catch up. Zimmerman first described the
solitary hair sticking out of most cells in an 1898 German paper, but the next
significant paper discussing primary cilia didn’t appear until 1961! We had to
wait for the electron microscope and molecular biology to catch up.
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The
electron microscope was the piece of
equipment
that allowed for deeper investigation
of
the primary cilium structure. Even though the
first
electron ‘scope was operational in 1931 (M.
Knoll
and E. Ruska, inventors), it still took 30 years
to
turn it’s power on the primary cilium. Was it
considered
just an immotile cilium, or did someone
suspect
it had more jobs to do? Molecular biological
techniques
in the 1990’s answered that question and
led
to an explosion of study on the solitary antenna
of
most cells.
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You know that your brain works by transmitting electrical
impulses through specific neural pathways. But chemistry in the brain is just as
important as electricity. Hormones, neurotransmitters, even non-chemical
signals like temperature and flow are converted to chemical and electrical
signals via primary cilia.
As with so many other things, we learn biology best by
studying what happens when things go wrong. You won’t believe the diseases that
are being linked to this most innocuous of cell structures. Without any
exaggeration, primary cilia make you smart, skinny, and happy. Let’s find out
how.
Inside your brain are fluid filled cavities called ventricles. The ventricular system of
the brain is connected through the ventricles and travel part way down your
spinal column as well. They are filled with cerebrospinal fluid (CSF) and this fluid has many functions.
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Here
is the ventricular system of the vertebrate
brain.
Blue = lateral ventricles, cyan= inter-
ventricular
foramina, yellow = third ventricle,
red
= cerebral aquaduct, purple = fourth ventricle,
green
= central canal. What the image doesn’t show
is the
connection that allows CSF to surround the
brain
in the subarachanoid space, between the
brain
and the skull. This is where 85% of the
CSF
can be found.
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The cells that line the ventricles are neuroepithelial cells
called ependymal cells. They have
motile cilia (2˚ cilia), as well as microvilli
– which we learned last week aren’t cilia-like at all. The ependymal cell cilia
beat in a specific direction depending on where they are in the system. The
coordinated beating keeps the CSF flowing through the ventricles; flow is key
to its functions.
The microvilli have a different job; they absorb CSF and
transfer it into the brain tissue as a way of keeping the brain in the proper
chemical environment. In this way, it helps mediate the CSF functions described
above.
But there is a second cell type in the ependymal layer. B1 cells are pre-ependymal cells. When
called upon, they differentiate to form more ependymal cells. These B1 cells
are located just below the ependymal layer, but they have small areas where
they stick up and touch the CSF. And here they each have a primary cilium.
A 2014 study showed that the B1 primary cilia actually
control the function of the ependymal cell motile cilia. And since the motile
cilia of B1 cells control pressure and flow of CSF in the ventricular system,
it’s really the primary cilia who are in charge.
Because of this, a problem with the motile cilia of the
ependymal cells or the primary cilia
of B1 cells leads to disrupted CSF control and hydrocephalus. Hydrocephalus (hydro = water, and cephalo = brain) leads to increased intracranial pressure and this is
lethal for neural tissue. Mental retardation, other complications, and death
are the results of hydrocephalus.
So we already see that these short projections that were
ignored for so long have one crucial job in the brain. But there’s more. It
isn’t just their presence that matters; it’s their length.
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Huntington’s
chorea, or just plain Huntington’s
disease,
is insidious; it’s lethal and there is no
treatment.
It results in debilitating movements of
the
motor system. Even though the genetic mutation
is
with you your whole life, the disease doesn’t show
up
until middle age, probably after you have had kids.
So
you don’t know that you passed it on until it’s too
late.
There is a test for it – would you want to know
if
you had it?
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A genetic problem in a single cilial gene leads to a disease called
Huntington’s chorea (means dance for
the strange movements the patients make). A 2011 paper showed that the mutation
lengthens both motile and primary cilia in the ventricles. This in turn alters the beating of the
motile cilia and disrupts flow of the CSF. This isn’t the only defect in the
disease, but changes in CSF are thought to exacerbate the disease.
Interestingly, the changes in intracranial pressure via
primary cilia changes can lead to obesity. How could CSF and eating be
connected? Well, in a couple of ways – let’s investigate further.
There are several syndromes that include obesity in their
list of symptoms, diseases like Bardet-Biedl syndrome, Carpenter syndrome, and
others. The commonality in these diseases is that there are mutations that
affect some aspect of primary cilia function, production, or maintenance. Changes
in primary cilia can affect your weight?
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No
big message here, just thought the primary cilium
looked
like Alfalfa from Our Gang. Length is crucial for
primary
cilia– I suppose Alfalfa kept his a particularly
length
too.
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POMC neurons make alpha-MSH and multifunctional hormone.
This is released from the POMC neurons and acts on downstream pathways to tell
you to stop eating. If the primary cilia on the POMC neurons are too short or
absent, you experience hyperphagia (hyper = beyond, and phagia = eating), ie. compulsive eating. You just can’t stop
eating.
Many of the syndromes that start as primary cilia problems
show both compulsive eating AND hydrocephalus. So this explains how
hydrocephalus may affect obesity in one, way, but there’s another. If you have
a brain injury that damages the ependymal or B1 cilia, then hydrocephalus might
result. The POMC neurons are located right next to the third ventricle, so
increased intracranial pressure during hydrocephalus can damage them and lead to
compulsive eating directly.
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Notice
how close the third ventricle is to the POMC
neurons
of the hypothalamus. Hydrocephalus alone can
induce
changes in primary cilia length on them so they
won’t
respond to insulin or leptin. Then you
eat
compulsively.
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So, here we have a miniscule part of your neurons cells that, if
not exactly the needed length, can take away your intelligence AND your
beach-ready physique. But it gets worse.
Many of these same ciliopathies
(disease of cilia function) are also associated with clinical depression. The
problem is, we don’t know how they
lead to depression. Depression is often thought to be a problem of serotonin
signaling in the brain, but it can be multifactorial. Here’s one interesting
result though – lithium lengthens primary cilia.
Lithium is used
to treat depression, and we don’t yet really know why it works. But lithium also increases the length of primary cilia in many cell types of the brain.
Considering that many depressed people gain weight, could depression and
compulsive eating be linked by primary cilia length? Lithium treats them both.
This could explain why people coming out of depressive episodes often lose
weight.
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The
popular soft drink &-Up contained lithium citrate
until
1950. It is used as a mood stabilizer now, and we
know
it promotes weight gain, but here they advertize it
as
slenderizing. The name, 7-Up, is a mystery, but the
atomic
mass of lithium is seven - hmmm.
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Sounds like we’re really on to something here.
People who are treated for depression and get better often lose weight. Is it
because they a) feel better and then do more activity, or is it because 2) their POMC
primary cilia are longer and this suppresses their appetite?
No way for number two. Biology is never that
simple. It turns out that one of the major side effects of lithium treatment
for mood stabilization is weight gain.
It has to do with lithium affecting the function of the thyroid gland, this
being one of the major regulators of your metabolism. Your metabolism slows
down and you gain weight.
Maybe if we just inject the lithium into the brain
ventricles…. You want to volunteer for that weight loss program?
Next week, how can primary cilia control whether mankind
ever gets to step foot on Mars or help the Enterprise on its five year mission
to seek out new worlds? By controlling bones….. no, not Bones McCoy, just
bones.
For
more information or classroom activities, see:
Ventricular
System –
Huntington’s
disease –
POMC
–
Lithium
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