U.Va.'s Xiaowei Lu Examines the Precise Nature of Hearing

Jan. 19, 2007 -- The ear is one of the most elaborate and extraordinary structures in the body. Sound waves from our surroundings pass through a series of delicately balanced bones and exotic fluids before arriving at a set of exquisitely sensitive hair cells, aligned in precise rows along the organ of Corti. These hair cells perform a remarkable task: they transform a mechanical impulse into an electrical signal that, carried to the brain, is interpreted as sound. In the language of science, they are “a mechanotransduction apparatus.”

Xiaowei Lu, assistant professor of cell biology, has been drawn to these cells — not specifically to tease out the process of mechanotransduction — but to address the fundamental mystery of their development. She is using mouse genetics to determine how these cells manage to organize themselves exactly so that their hair bundles, the part of the cell that senses motion, all face in the same direction. This tight formation is absolutely essential for hearing. If the cells are not aligned uniformly, the signal from the organ of Corti will be helplessly confused; a person with this condition would have impaired hearing.

The uniform alignment of hair cells is an example of planar cell polarity (PCP). Typical
AAA batteries have positive and negative poles at their ends. In order for a digital camera to work, for example, all the batteries have to be inserted with the positive poles touching the positive contacts. By analogy, auditory hair cells would have ‘positive’ and ‘negative’ sides. PCP is a fundamental biological phenomenon, found in plants and animals at all levels of complexity. Understanding the underlying mechanism that drives this process can shed light on how multicellular organisms develop.

Thanks to a Fund for Excellence in Science and Technology (FEST) grant from U.Va., Lu has been able to combine a number of approaches to uncover the components of PCP and to find out how they work together. She uses gene trapping, a method of inducing mutations at precise locations in the genome, and she analyzes the proteins these genes produce. “If the protein looks interesting, I produce a knockout mouse in which the gene is inactive and see how the mouse is different,” Lu says.

Lu can also grow the mouse auditory epithelium in a laboratory dish, producing an organ that is virtually identical to one developed in a living mouse. This explant system creates a host of opportunities for Lu. “We can mark the different molecules involved in the process with fluorescent tags and use live imaging to see how proteins move   through hair cells to produce asymmetry,” she says. “We can also insert genes of interest and see how they affect molecular dynamics and hair bundle orientation.”

Lu has found that the hair cells in knockout mice that lack the ability to produce protein tyrosine kinase 7 (PTK7) don’t face in the same direction. “Our current focus,” Lu says, “is to figure out more about how PTK7 regulates PCP and guides the   development of tissues and organs.”

In her work, Lu is able to take advantage of the world-class expertise at U.Va. about inner ear development and developmental biology in general. “This department fits me like a glove,” she comments. “I’ve greatly benefited from the suggestions and support of my colleagues.”