Left: Organ of Corti from normal (control) mice. Hair cells and their supporting cells alternate in a checkerboard-like pattern. Right: Organ of Corti in Nectin KO mice. The top row of images was taken at 12 days after birth and the bottom row at 28 days after birth. At 2 weeks of age, hair cells in Nectin KO mice disappeared due to apoptosis (cell death). White arrows indicate where hair cells attach to each other. Credits: Katsunuma S, Togashi H, Kuno S, Fujita T, Nibu KI (2022) Deafness in mice due to disruption of cochlear auditory epithelial patterns. front. Cell development organism. 10:1073830
A Japanese research group has revealed for the first time that the checkerboard arrangement of cells in the organ of Corti in the inner ear is essential for hearing. This finding provides new insights into how hearing works in terms of cellular self-organization and also allows us to better understand different hearing impairments.
The research group included Assistant Professor Hidetome Togashi of Kobe University Graduate School of Medicine and Dr. Sayaka Katsunuma of Hyogo Prefectural Kobe Children’s Hospital.
These research results were published online The forefront of cell developmental biology December 8, 2022.
main point
- The organ of Corti in the inner ear has two types of cells arranged in a checkerboard mosaic pattern. Hair cells and their supporting cells involved in hearing. However, the relationship between this checkerboard pattern and auditory function remained unclear for a long time.
- In mice in which the cells of the organ of Corti failed to form this checkerboard pattern, only the hair cells died (apoptosis), resulting in hearing loss.
- For the first time in the world, it was understood that the checkerboard arrangement plays a fundamental structural role in maintaining hair cells and their function.
- This cellular mosaic pattern has been 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 function and impairment of various sensory organs.
Research background
The cochlea of the inner ear is an organ necessary for hearing sound, and one of them is the organ of Corti (*1). Looking at the organ of Corti from above under a microscope, you can see that the two types of cells are arranged in a precise order, like a chess or checkerboard. Hair cells that transmit sound waves to the brain are separated by supporting cells that prevent them from contacting each other. This checkerboard arrangement has been thought to be necessary for the proper functioning of the organ of Corti, but the relationship between this pattern and auditory function has long remained unclear.
This research group has previously revealed that this inner ear checkerboard is formed by a cell separation mechanism that allows hair cells and supporting cells to align correctly. Hair cells and supporting cells each express different types of cell adhesion molecule nectins. This causes hair cells and supporting cells to adhere more strongly to each other than two hair cells or two supporting cells. This property arranges hair cells and supporting cells in a checkerboard pattern. Mouse models in which one of these nectin molecules is not functional have altered properties and incorrect checkerboard formation. In this study, researchers used these mice to investigate the relationship between checkerboard arrangement of cells and hearing function.
research method
The research group compared normal (control) mice with mice in which one type of Nectin is not functioning properly (Nectin-3 KO mice, hereafter referred to as Nectin KO mice). There was no difference between mice in the numbers of hair cells and supporting cells in the organ of Corti at birth. However, there were differences in how the two types of cells adhered to each other. In Nectin-3 KO mice, hair cells adhere to each other (which normally does not 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 used the auditory brainstem response (ABR) method to measure hearing in Nectin KO mice aged 1 month or older (*2). This test revealed that Nectin KO mice were moderately deaf, demonstrating that this deafness was caused by inner ear abnormalities.
The researchers next examined the organ of Corti in Nectin KO mice that underwent ABR testing and found that the number of hair cells was reduced by about half. Next, we tried to find out why only the hair cells (and not the supporting cells) disappeared. We discovered that apoptosis (*3) of hair cells occurs 2 weeks after birth. In addition, when we examined the traces of apoptosis, we found that cell death occurred in many cells that had adhered to each other. This led the researchers to speculate that hair cells adhering to each other, which does not normally occur, triggered apoptosis.
Epithelial tissues, including the organ of Corti, have tight junctions between each cell. These tight junctions not only connect cells but also prevent various molecules (including ions) from passing between cells. Without these tight junctions in the organ of Corti, hair cells cannot function properly, resulting in cell death and hearing loss. Nectin KO mice failed to properly form tight junctions where hair cells adhered. However, tight junctions formed correctly between hair cells and supporting cells. Normal cell function was maintained as long as the two hair cells did not stick together. In other words, hair cell apoptosis was induced only where hair cells adhered to each other abnormally and tight junctions were not properly formed. These results demonstrate for the first time that the checkered pattern of hair cells and supporting cells found in the organ of Corti functions as a basic structure that prevents hair cells from adhering to each other and protects hair cells and their functions. I made it
Further research
Nectin is the causative gene for ectodermal dysplasia (*4) in Margarita Islet. In addition to cleft lip or palate and intellectual disability, hearing loss has also been reported in some cases of this genetic disorder. Therefore, the results of the current study may provide a new explanation for some cases of hearing loss of unknown cause.
This study focused on hearing and demonstrated the physiological importance of the checkerboard-like mosaic pattern of cells in the organ of Corti. However, other sensory cells that respond to external stimuli and their respective supporting cells are also arranged in the same type of alternating mosaic pattern. These mosaic patterns are found in sensory organs such as the olfactory epithelium, which controls smell, and the retina, which controls 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. It is made by self-organization due to differences in Therefore, research focused on cellular self-organization in sensory organs will increase our knowledge of sensory function and deepen our understanding of the various associated diseases.
Glossary
- Organ of Corti: A sensory organ that controls hearing. Located inside the cochlea in the inner ear.
- Auditory Brainstem Response (ABR): A method of recording the brain waves that occur when you hear a sound. ABR is not only used for human neonatal hearing testing, but can also be used in mice and other animals.
- Apoptosis: A type of programmed cell death or cell suicide that occurs in multicellular organisms.
- Ectodermal dysplasia of Margarita Island: An inherited disorder caused by mutations in the Nectin-1 gene. The main symptom is cleft lip or palate with intellectual disability.
reference
Sayaka Katsunuma, Hide Togashi, Shuhei Kuno, Takeshi Fujita, Kenichi Niu, “Deafness in mice with disruption of auditory epithelial patterning in the cochlea,” December 8, 2022, The forefront of cell developmental biology.
DOI: 10.3389/fcell.2022.1073830
Acknowledgments
This work was funded by the following organizations: Grants-in-Aid for Scientific Research from the Japan Society for the Promotion of Science (JSPS) (grant numbers: 18H04764, 18K09319, 19H04965, 22K19331); JPMJPR1946), and the Takeda Pharmaceutical Science Foundation.
