The inner ear cells are arranged in a checkerboard shape that allows us to hear sound

For the first time, a Japanese team has discovered that the checkerboard-like arrangement of cells in Corti, an organ of the inner ear, is essential
for hearing.
This discovery provides new insights into how hearing works from the perspective of cellular self-organization and will also lead to a better understanding of various hearing loss disorders
.

The research team included TOGASHI Hideru, an assistant professor at Kobe University's Graduate School of Medicine, and Dr.
KATSUNUMA Sayaka of Kobe Children's Hospital in Hyogo Prefecture.

The findings were published online December 8, 2022, in the journal Frontiers in Cell and Developmental Biology
.

essentials

• In the Corti organ of the inner ear, there are two types of cells arranged in a checkerboard-like mosaic pattern; Hair cells are responsible for hearing and support cells
  .
  However, the relationship between this checkerboard pattern and hearing function has been unclear
  .
  

• In mice where cells in Corti organs could not form this checkerboard-like pattern, only hair cells died (apoptosis), which led to deafness
  .
  

• For the first time in the world, it was recognized that the checkerboard layout plays a fundamental structural role in protecting hair cells and their functions, as this arrangement prevents hair cells from sticking
  to each other.
  

• This mosaic pattern
  of cells is observed in various sensory organs in many different species of animals.
  Understanding the mechanisms behind how cellular self-organization forms these mosaic patterns will help elucidate the mechanisms behind the functions and diseases of various sensory organs
  .
  

Research background

The cochlea of the inner ear is necessary for hearing sound, and inside it are the Corti organ (*1).

When the Corti organ is viewed from above under a microscope, two types of cells can be seen arranged in a precisely ordered layout, similar to chess or a chess board
.
The hair cells that transmit sound waves to the brain are separated by support cells, which prevent hair cells from touching
each other.
Although this checkerboard arrangement has long been thought to be necessary for Corti's organs to function properly, the relationship between this pattern and hearing function has long been unclear
.

The team previously revealed that this inner ear checkerboard is formed by a cell separation mechanism that allows hair cells and supporting cells to line up correctly
.
Hair cells and supporting cells each express different types of cellular adhesion molecular ligins
.
This results in one hair cell and one supporting cell being more tightly bound
together than two hair cells or two supporting cells.
This property causes hair cells and support cells to be arranged in a checkerboard-like
pattern.
In a mouse model, if one of the nectin molecules has no function, its properties change and the checkerboard pattern does not form
correctly.
In this study, the researchers used these mice to study the link between the
checkerboard arrangement of cells and hearing function.

Research methods

The team compared
normal (control) mice with a type of mouse with an unfunctional type of linkerin (licin-3 KO mice, referred to simply as ligacin KO mice).
After birth, no difference
was immediately observed in the number of hair cells and supporting cells in the Corti organs of mice.
However, there are differences in how easily these two types of cells adhere to each other; In nectin-3 KO mice, hair cells adhere together (which does not normally occur), resulting in an abnormal
checkerboard pattern.
At this point, the researchers hypothesized that testing the hearing of these mice might reveal a relationship between
hearing and checkerboard patterns.
They measured hearing (*2) in nectin KO mice older than one month old using the auditory brainstem response (ABR)
method.
The test showed moderate deafness in nectin KO mice, suggesting that hearing loss was caused
by an abnormality in the inner ear.

The researchers then examined the Corti organs of nectin KO mice that underwent ABR testing and found that the number of hair cells was reduced by about half
.
Next, they set out to find out why only hair cells (and not supporting cells) had disappeared
.
They found apoptosis of hair cells after 2 weeks of age (*3).

In addition, examination of traces of apoptosis revealed that cell death
occurred in many cells that adhered to each other.
This led the researchers to speculate that it was hair cells that adhered to each other (which usually does not happen) that caused apoptosis
.

In epithelial tissue, which also includes the Corti organ, there are tight junctions
between each cell.
These tight connections not only connect cells, but also prevent various molecules, including ions, from being passed
between cells.
If Corti's organs don't have these tight connections, the hair cells can't work properly, the cells die, and hearing is lost
.
In nectin KO mice, tight junctions are not formed
correctly where the hair cells adhere.
However, tight junctions
do form between hair cells and supporting cells.
As long as the two hair cells do not stick together, normal cell function is maintained
.
In other words, apoptosis of hair cells only occurs
where hair cells adhere to each other abnormally and do not properly form tight junctions.
These results reveal for the first time the checkerboard-like structure of hair cells and supporting cells found in Corti organs as a basic structure that protects hair cells and their function
by preventing them from attaching to each other.

Further research

Nectin is a causative gene for Margaret Island ectodermal dysplasia (*4).

In addition to cleft lip and palate and intellectual disability, some cases of this genetic disorder have also been reported
deafness.
Therefore, the results of the current study may provide new explanations
for some cases of deafness whose cause is unknown.

This study focused on hearing and demonstrated the physiological significance
of the cellular checkerboard mosaic pattern in Corti's organs.
However, other sensory cells that respond to external stimuli and their respective supporting cells are arranged
in the same alternating mosaic pattern.
These mosaic patterns are found in sensory organs, such as olfactory epithelial cells, which are responsible for smell, and retina
, which is responsible for vision.
The fact that these mosaic patterns are found not only in mammals but also in a variety of other organisms suggests that they are functionally important
.
Mosaic patterns in sensory tissues are generated
through self-tissue due to differences in cell-to-cell adhesion.
Therefore, focusing on the cellular self-organization of sensory organs will increase our understanding of the function of sensory organs and promote our understanding of
various related diseases.

Journal Reference:

1. Sayaka Katsunuma, Hideru Togashi, Shuhei Kuno, Takeshi Fujita, Ken-Ichi Nibu.
   Hearing loss in mice with disruption of auditory epithelial patterning in the cochlea.
   Frontiers in Cell and Developmental Biology, 2022; 10 DOI: 10.
   3389/fcell.
   2022.
   1073830