For cells to form functional organs, they must not only multiply but also migrate to the correct locations and settle in a particular orientation. During embryo development, cells remain in constant motion and division. If cells fail to arrange or align correctly, organs could either be defective or fail to function properly. And yet, cells somehow manage to find their place and align with remarkable precision—a biological feat that continues to puzzle scientists.
Recent research from Dr. Raj Ladher’s group at NCBS shows how cells in a developing inner ear organ organise and orient themselves with precision. By studying chick and mouse embryos, the team identified key molecular players that guide this process and discovered that these molecules are not limited to the ear but play a role throughout the body
“Our inner ear has a tiny organ called the cochlea that sends sound signals to the brain. It contains two main types of cells–hair cells and supporting cells–arranged in a specific way, both in how they sit and how they are oriented,” says Anubhav Prakash, the lead author of the study. While the cochlea is unique to mammals, other vertebrates like birds have similar organs, such as the basilar papilla, that serve the same purpose. Hair cells are the sensory cells that detect sound vibrations and trigger nerve signals, while supporting cells surround them, providing structural and nutritional support. On top of each hair cell sits a hair bundle–a tiny, asymmetrical bundle of protrusions - like bristles on a toothbrush, which responds to sound waves. “For hearing to work properly, these cells must follow a precise layout, and the hair bundles need to face the right direction. If this arrangement goes wrong during development, it can lead to hearing disorders like sensorineural hearing loss, where the sound reaching the inner ear can’t be processed correctly,” says Prakash.a
In mice and chicks, all the cells that make up the cochlea are formed very early during embryonic development. During the later stages of development, these cells, instead of multiplying, transform to find different types of cells taking up the right positions and orientations needed for proper hearing. This coordinated cell movement reshapes the cochlea - from a simple, unstructured form into the elongated, coiled organ seen in adults.
In the basilar papilla, Prakash and his team examined myosin II, a protein commonly found at the junctions where cells meet. In its phosphorylated form, myosin II stiffens these junctions, acting like a tightening rope between neighbouring cells. The team discovered that, unlike in other tissues where junctions usually carry either mono- or di-phosphorylated myosin uniformly, the basilar papilla showed an unusual pattern: some junctions were rich in di-phosphorylated myosin, while others had almost none. This uneven distribution had never been observed before. When the researchers blocked this phosphorylation process, the tissue failed to develop correctly. “The stiffer junctions created by enriched myosin phosphorylation, and the softer, more fluid ones without it, together generate a kind of stretching tension across the tissue,” explains Prakash. “This tension helps shape the organ and guide cells into their correct positions.”
In mice, this process is regulated by an additional layer of control involving adhesion molecules—cell-surface proteins that govern how cells attach. These molecules ensure specificity, allowing only cells with the same adhesion molecules to become neighbours and keep the cells in the right spots.The researchers also investigated whether the parallel processes of cell positioning and orientation were regulated by a common molecular system. To test this, they used CRISPR to delete Vangl2, a gene known to control cell orientation. They found that without Vangl2, both the directional alignment and spatial arrangement of cells were disrupted, suggesting that the mechanical forces and molecular cues at work are not acting separately.
“This work highlights a fundamental principle: organogenesis is driven by the integration of mechanical forces and molecular signals, and neither is a sufficient explanation independently. The challenge lies in understanding how this interplay occurs across diverse tissues and using it to correct developmental errors. By uncovering how cells ‘sense’ and ‘negotiate’ their positions within a dynamic tissue landscape, we move closer to being able to re-engineer complex organs in a dish,” says Dr Raj Ladher, the principal investigator of the study.
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