Hearing is one of our five senses, allowing us to listen to the sounds of our universe. This ability is unlocked by an incredibly complex structure inside our ears. One part of the complex structure is the part that detects sound, called the auditory epithelium. This tissue lines the inner ear like a delicate carpet. It comprises two main types of cells: the sensory hair cells that detect sound vibrations with tiny hair bundles and supporting cells that surround and help the hair cells.
These cells must be arranged in a specific pattern for us to hear clearly. Every hair cell must be surrounded by supporting cells. All the hair bundles on the hair cells also need to point in the same direction across the tissue, giving the whole structure a planar polarity crucial for sensitive hearing. This precise arrangement develops even while the cells move and rearrange themselves during the ear's growth. Scientists have known this happens, but the big question has been: how do cells simultaneously coordinate these two levels of order – position and orientation – especially in a tissue of different cell types?
New research from the National Centre for Biological Sciences (NCBS), University of Geneva, Switzerland, and the University of Trans-Disciplinary Health Sciences and Technology, Bengaluru, dives deep into that question. They used the inner ear of chicks, which is a great model for studying how this tissue develops.
They found that the precise organisation of the auditory epithelium is driven by specific mechanical forces acting at the boundaries where cells touch each other, called cell-cell junctions. It's like the cells are subtly pulling and pushing on their neighbours with different strengths, and these forces create a pattern that guides the tissue's development. Tiny molecular motors called non-muscle myosin II (NMII) are key players in generating these forces. NMII acts like a miniature muscle, pulling on the cell's internal scaffolding called actin filaments. The strength of this pull depends on whether a small part of NMII, called the regulatory light chain (RLC), has one or two phosphate groups attached, like a molecular switch that changes the motor's power.
The researchers discovered that the junctions between two supporting cells (SC-SC junctions) have a lot of NMII with two phosphate groups (pp-RLC), making these junctions stronger and less wobbly or prone to length changes. In contrast, the junctions between a hair cell and a supporting cell (HC-SC junctions) have more NMII with only one phosphate group (p-RLC), making them weaker and more flexible. They used live imaging to watch these junctions in developing ear tissue and saw that SC-SC junctions fluctuate less, confirming they are under more tension.
To understand how these different pulling strengths affect the tissue structure, they used a computer model that simulates cells as polygons connected by junctions, like a honeycomb. By giving the SC-SC junctions higher contractility or pulling strength in the model, they could reproduce the experimental observation that hair cells end up perfectly surrounded by supporting cells, just like in the real ear. This showed that the differential forces at the junctions are enough to create the correct positional order.
But what about the planar polarity – getting all those hair bundles to point correctly? Hair cells have their internal sense of direction linked to the position of their hair bundle. The new study found that a molecular complex called LGN-Gai, which is known to help set up this internal polarity is located at the HC-SC junctions near the hair bundle. This complex seems to create an asymmetry in the p-RLC on the HC-SC junction – the part of the junction away from the hair bundle has more p-RLC and is weaker. So, each hair cell has a slightly weaker pull on one side.
However, aligning all hair cells across the entire tissue requires coordination. The researchers found that the stronger SC-SC junctions also play a role here. The SC-SC junctions aligned with the overall tissue axis (proximal-distal axis of the ear) have higher levels of strong pp-RLC and are more contractile. A key protein involved in planar cell polarity, Vangl2, is also enriched on these axis-aligned SC-SC junctions and helps regulate the pp-RLC.
Vangl2 provides a compass for the tissue, telling the SC-SC junctions which way to be strongest. This creates lines of stronger tension across the tissue, and the weaker sides of the hair cells (where p-RLC is enriched) seem to align with these lines of tension, causing the hair bundles to point in the correct direction. They showed that disrupting Vangl2 or the LGN-Gai complex messed up the positional order and the planar polarity, highlighting how interconnected these processes are. The spatial arrangement of the cells itself also feeds back and influences where Vangl2 is enriched, adding another layer of coordination. Even the slight natural curve of the ear tissue helps bias the direction of polarity.
Earlier ideas suggested that overall cell flow or long-range repulsive forces might be the main drivers of organisation in the mouse ear. While those might play some role, this research provides strong experimental and theoretical evidence that local junctional mechanics, controlled by specific molecular players like different forms of NMII and PCP proteins like Vangl2, are sufficient to generate *both* the precise positional pattern and the tissue-wide orientation in a multi-cell type epithelium like the auditory epithelium. Previous models for planar polarity often focused on tissues with only one cell type, so showing how different cell types coordinate through their junctions is a key step.
However, the research also points to areas for future study. While successfully generating positional order and nematic or aligned but not strictly directional polarity, their computer model needed additional cues like tissue curvature to achieve the complete polar (directional) alignment seen in the real ear. This suggests that other factors, like biochemical gradients or other parts of the planar cell polarity pathway, are needed to fully refine and stabilise the polarity direction, especially later in development. The exact upstream signal that tells Vangl2 and the SC-SC junctions which way the tissue axis is remains an open question, although gradients and Wnt signalling are potential candidates.
Understanding how the inner ear builds itself with such incredible precision is vital as defects in the development and organisation of these sensory tissues cause many forms of congenital hearing loss. By uncovering the fundamental mechanical principles and molecular players that guide this process, this research provides crucial insights into the causes of these conditions.
This research article was written with the help of generative AI and edited by an editor at Research Matters.