Wednesday, February 11, 2015

Thinking Skinny Thoughts Won’t Help

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.

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?
In some cases we are shown the truth but don’t recognize it, as with Gregor Mendel’s discovery of the laws of genetics. Using his various pea plants, the Augustinian friar’s work was presented in 1865 and published 1866 – and then was forgotten for decades.

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.

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.
Last week we discussed how primary cilia are like the antennae of cells, they stick out into the extracellular environment and react to flow pressure (kidney tubule cells), vibration (hair cells of cochlea), chemicals (hormones and such) or even light (photoreceptor cilia). Now we’re realizing some of the amazing things that this sensing controls – your brain for instance.

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.

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.
Like an internal helmet, one of the functions of the CSF is to cushion the brain, acting as a shock absorber. But it does so much more than that. CSF also stabilizes the chemistry of the brain, and helps with blood perfusion by mediating the pressure in the cranium. Finally, the CSF removes waste products from the central nervous system.

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.

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?
Primary cilia have specific lengths in different cell types. Too long or too short and it’s like they aren’t there at all. In kidney tubule cells, increased urine flow bends the cilia, so they transmit signals to the cells, but too much signaling would be bad. Increased flow shortens the primary cilia so they become less responsive, and this is the control mechanism. In the ependymal layer, both motile and primary cilia length are crucial.

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?

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.
A 2007 paper narrowed down the subset of cells where the primary cilia are disrupted by putting different primary cilia under the control of different regulators in mice. Then they could wait until the mice grew up and turn off the primary cilia in various cell types. They found that it is just the POMC neurons in the hypothalamus that regulate obesity. This means that it is a brain and behavioral issue, not a problem with energy metabolism in the body.

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.

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.
The question remains as to what signal(s) the POMC primary cilia are sensing in order to tell you to stop eating. It is probably several, chemicals that say you are full or have enough fat. Leptin, the hormone released by fat cells is certainly one of them. A 2014 study in obese mice with leptin deficiency or leptin resistance proved this. The primary cilia on POMC neurons in hypothalamus are short in these mice due to lack of leptin signaling, and therefore they don’t work well and don’t stimulate alpha-MSH release.

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.

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.

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.

Tong, C., Han, Y., Shah, J., Obernier, K., Guinto, C., & Alvarez-Buylla, A. (2014). Primary cilia are required in a unique subpopulation of neural progenitors Proceedings of the National Academy of Sciences, 111 (34), 12438-12443 DOI: 10.1073/pnas.1321425111

Han, Y., Kang, G., Byun, K., Ko, H., Kim, J., Shin, M., Kim, H., Gil, S., Yu, J., Lee, B., & Kim, M. (2014). Leptin-promoted cilia assembly is critical for normal energy balance Journal of Clinical Investigation, 124 (5), 2193-2197 DOI: 10.1172/JCI69395

Davenport JR, Watts AJ, Roper VC, Croyle MJ, van Groen T, Wyss JM, Nagy TR, Kesterson RA, & Yoder BK (2007). Disruption of intraflagellar transport in adult mice leads to obesity and slow-onset cystic kidney disease. Current biology : CB, 17 (18), 1586-94 PMID: 17825558

Keryer, G., Pineda, J., Liot, G., Kim, J., Dietrich, P., Benstaali, C., Smith, K., Cordelières, F., Spassky, N., Ferrante, R., Dragatsis, I., & Saudou, F. (2011). Ciliogenesis is regulated by a huntingtin-HAP1-PCM1 pathway and is altered in Huntington disease Journal of Clinical Investigation, 121 (11), 4372-4382 DOI: 10.1172/JCI57552

Miyoshi, K., Kasahara, K., Miyazaki, I., & Asanuma, M. (2009). Lithium treatment elongates primary cilia in the mouse brain and in cultured cells Biochemical and Biophysical Research Communications, 388 (4), 757-762 DOI: 10.1016/j.bbrc.2009.08.099

For more information or classroom activities, see:

Ventricular System –

Huntington’s disease –


Lithium -

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