By Albert Edge, Ph.D., and Alain Dabdoub, Ph.D
The goal of the Hearing Restoration Project (HRP) is to determine how to regenerate inner ear sensory cells in humans to eventually restore hearing for millions of people worldwide. These sensory cells, called hair cells, in the cochlea detect and turn sound waves into electrical impulses that are sent to the brain. Once hair cells are damaged or die, hearing is impaired, but in most species, hair cells spontaneously regrow and hearing is restored. The HRP is aiming to enable this ability in humans.
All cells develop through a chain of events triggered by chemical signals (proteins) from outside the cell. The signals kick off responses inside the cell that can change the cell’s ability to proliferate (grow and divide) and differentiate (take on specialized functions).
The Wnt signaling pathway, a sequence of events triggered by the Wnt protein, helps guide inner ear cell development, including the proliferation of cells that differentiate into the hair cells and supporting cells necessary for hearing and balance. But in mice and other mammals, inner ear cell proliferation does not continue past newborn stages.
Underscoring their importance in evolutionary terms, Wnt signals occur across species, from fruit flies to humans—the “W” in Wnt refers to “wingless”—and Wnt signaling is guided by dozens of genes. Albert Edge, Ph.D., Alain Dabdoub, Ph.D., and colleagues performed a comprehensive screen of 84 Wnt signaling-related genes and identified 72 that are expressed (turned on) during mouse inner ear development and maturation. Their results appeared in the journal PLoS One this February.
The Wnt signaling network has three primary pathways. Two are known to be integral to the formation of the mammalian inner ear, including the determination of a cell’s “fate,” or what type of cell it ultimately turns into. This is particularly significant because the inner ear’s sensory epithelium tissue is a highly organized structure with specific numbers and types of cells in an exact order. The precise arrangement and number of hair cells and supporting cells is essential for optimal hearing.
The relationship between the Wnt-related genes, the timing of their expression, and the various signaling pathways that act on inner ear cells is extremely complex. For instance, the composition of components inside a cell in addition to the cell’s context (which tissue the cell is in, and the tissue’s stage of development) will influence which pathway Wnt signaling will take. It is known that inhibiting the action of Wnt signaling causes hair cells to fail to differentiate.
The new research complements previous chicken inner ear studies of Wnt-related genes as well as a recent single-cell analysis of the newborn sensory epithelium in mice (conducted by HRP scientist Stefan Heller, Ph.D., and colleagues). Comprehensively detailing these 72 Wnt-related genes in the mouse cochlea across four developmental and postnatal time periods provides a deeper understanding of a critical component of hair cell development, bringing the HRP closer to identifying genes for their potential in hair cell regeneration.
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