Cilia are still poorly understood

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(A) Scanning electron micrograph of motile cilia located on the ependymal cells that line the brain ventricles. Insert shows higher magnification of motile cilia. (B) Immunofluorescence micrograph of primary cilia (green) located on isolated renal tubule. Nuclei are shown in blue. Insert is a scanning electron micrograph looking into a renal tubule. (C) Architecture of cilia (primary and motile) and the basal body. (D) Intraflagellar flagella (ciliary) transport along the axoneme. Anterograde movement of the intraflagellar transport (IFT) particle is mediated by a heterotrimeric kinesin (kinesin-1) complex, whereas retrograde transport is mediated by a cytoplasmic dynein.

The ciliary apparatus is connected to cell cycle progression and proliferation, and cilia play a vital part in human and animal development and in everyday life.

The length of a single cilium is 1-10 micrometres and width is less than 1 micrometre.

Cilia are broadly divided into two types. They function separately and sometimes together:

Motile (moving) cilia
Source: Amelia Shoemark

Motile‘ (or moving) cilia are found in the lungs, respiratory tract and middle ear. These cilia have a rhythmic waving or beating motion. They work, for instance, to keep the airways clear of mucus and dirt, allowing us to breathe easily and without irritation. They also help propel sperm.

SEM of kidney primary cilium
Source: UT Southwestern MC

Primary cilia appear typically as single appendages microtubules on the apical surface of cells and lack the central pair of microtubules (e.g. in kidney tubules).

In the kidney, for example, cilia bend with urine flow and send a signal to alert the cells that there is a flow of urine.

In the eye, non-motile cilia are found inside the light-sensitive cells (photoreceptors) of the retina.

These cilia act like microscopic train-tracks, and allow the transport of vital molecules from one end of the photoreceptor to the other.

Structure and Function of Cilia

Cilium structure
Source: Miriam Schmidts, Institute of Child Health

Structurally, each cilium comprises a microtubular backbone – the ciliary axoneme – surrounded by plasma membrane (see figure below).

Motile cilia are characterized by a typical ’9+2’ architecture with nine outer microtubule doublets and a central pair of microtubules (e.g bronchi).

Primary cilia appear typically as single appendages microtubules on the apical surface of cells and lack the central pair of microtubules (e.g. in kidney tubules).

Ciliary proteins are synthesized in the cell body and must be transported to the tip of the axoneme.

This is achieved by Intraflagellar Transport (IFT), an ordered and highly regulated anterograde and retrograde translocation of polypeptide complexes (IFT particles) along the length of the ciliary axoneme.

Dysfunction or defects in motile and primary cilia are now understood to underlie a number of devastating genetic conditions – termed ciliopathies – which carry a heavy economic and health burden on individuals, families and society.

Much is still unknown about the structure and function of motile and primary cilia, but we believe that more research into these critically important cellular organelles will eventually bring about better ways to treat and help people whose lives are impacted by defective cilia.

People with ciliary defects can develop neurological conditions like hydrocephalus and scoliosis.

New research from the Yaksi group at Kavli Institute for Systems Neuroscience at the Norwegian University of Science and Technology (NTNU) shows that cilia are essential for the brain to develop normally.

An article now published in Current Biology reports insight into how cilia work and why they are so important for brain development.

The human brain has four fluid-filled cavities called ventricles, all of which are interconnected.

The ventricles are filled with cerebrospinal fluid, which is also produced here.

The cerebrospinal fluid is in constant motion, but the movement varies depending on activity.

“Several theories exist, but for many years this circulation of fluid has been recognized as supplying nutrients to the brain, while also removing waste products,” says senior researcher Nathalie Jurisch-Yaksi at NTNU’s Kavli Institute.

“The cerebrospinal fluid flow also contributes to transmitting molecular signals across the brain,” says Emre Yaksi, a professor at the Kavli Institute.

It would not be possible to conduct this kind of research on humans for ethical and practical reasons. Hence, the research group has chosen to do their research on zebrafish larvae, which are ideal for this type of research.

They are vertebrates just like humans, and exhibit often analogous processes to human brain development and function.

On a practical note, zebrafish are transparent during their larval stage. This means that it is possible to investigate brain development and function in astonishing detail without any intervention, and without causing them any pain. “We could even investigate each individual cell and cilia,” says Ph.D. candidate and co-author Christa Ringers.

The Yaksi group researchers found that groups of cells with cilia are organized in different zones of the ventricles, which together create a stable, directional flow of the fluid.

Heartbeat pulsations and body movements also affect the circulation of cerebrospinal fluid, but the movements of the cilia appear to provide a stable fluid flow within individual ventricles.

This flow is local, so it is largely limited to each of the ventricles. But at the same time, it seems that the compartmentalized flow is necessary to keep the ducts between the cavities open. “If we stop the cilia’s motion, the ducts close,” says Jurisch-Yaksi.

The fluid flow in each ventricle and the exchange of fluid between the different ventricles depend on whether the subject is at rest or moving. “We found surprisingly little exchange of fluid between the ventricles as long as the fish were at rest, even though the heartbeat pulsations caused some flow between them,” says Ph.D. candidate Emilie Willoch Olstad, the first author of the article in Current Biology. But all this changes during movement. Locomotion leads to a great degree of fluid exchange between the ventricles.

Cilia fall into one of two main groups, motile or non-motile, also called primary cilia. The Yaksi groups examined motile cilia. Unlike most other cilia in the human body that contribute to the transfer of fluids, such as the brush-like respiratory cilia that protect the lungs, the Kavli researchers found that the cilia along the brain ventricles of the developing zebrafish brain have a propeller-like motion, much like the tail of sperm.

The cilia may also indirectly contribute to keeping the brain young and healthy. New nerve cells are born near the wall of the fluid-filled brain ventricles. From here, they migrate throughout the brain. The differentiation of these newborn cells is believed to be influenced by nutrients and molecular signals that are distributed by the flow of the cerebrospinal fluid near the ventricular walls.

In zebrafish, the birth of new neurons, also called neurogenesis, happens not only in the developing brain, but also in adult fish. Recent studies have revealed that this kind of adult neurogenesis also happens in humans.

Studying the dynamic movements of fluids is extremely complicated and requires a multidisciplinary approach. Mathematicians, engineers and physicists are among those who can help understand how cilia movement occurs and generates flow. The Yaksi group at the Kavli Institute is eager to collaborate with engineers who could develop better analytical tools and computer models to study fluid circulation in the brain. They are actively looking for people and collaborators with the right skills.

The research is far from over. The next step is to see if it is possible to influence the brain function of the zebrafish by manipulating the cilia and vice versa. For example, how would the neural activity, or even circadian rhythms, change when cilia mediated flow is perturbed? The zebrafish are usually far more active during the day than at night. Would altering the cerebrospinal fluid flow change the way fish perceive and respond to their environment during different times of the day? These are the next questions the researchers plan to address.

More information: Emilie W. Olstad et al. Ciliary Beating Compartmentalizes Cerebrospinal Fluid Flow in the Brain and Regulates Ventricular Development, Current Biology (2019). DOI: 10.1016/j.cub.2018.11.059 

Journal reference: Current Biology search and more info website

Provided by: Norwegian University of Science and Technology search and more info website

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