Knockout Mouse Reveals Genetic Mechanism In Defective Mammalian Ear Developoment

This control mechanism, which involves the genes Jagged2 and Notch1, was identified in a collaborative effort by research teams headed by Dr. Matthew Kelley at the Georgetown University School of Medicine and Dr. Thomas Gridley at The Jackson Laboratory. The results are reported in "The Notch Signaling Pathway Mediates Hair Cell Development in the Mammalian Cochlea" in the March 1999 issue of Nature Genetics.

Dr. Gridley has conducted extensive research on the Notch signaling pathway and led the team that reported last year on developmental defects in Jagged2 knockout mice from The Jackson Laboratory. He describes the pathway -- first studied in the fruit fly -- as a molecular mechanism that mediates communication between cells as they differentiate during embryonic development. In humans, Notch pathway mutations have been implicated in cancer and in several inherited disease syndromes.

"This work clearly establishes that identical mechanisms to control the development of sensory cells operate in both mammals and in lower organisms, such as the fruit fly," said Dr. Gridley. "Such evolutionary conservation of mechanism emphasizes the importance of the Notch signaling pathway for normal development. This pathway is a key regulator controlling the proper development of many different cell types."

The mammalian inner ear, or cochlea, is lined with an intricate "mosaic" of alternating hair cells and non-sensory supporting cells. Normal hearing results when sound waves cause the tiny hairs to oscillate, and the movement is transmitted as electrical impulses through the hair cells to the brain.

Drs. Kelley and Gridley and their colleagues found that mice without Jagged2 exhibit a significant increase in hair cell density compared with normal mice, and have fewer supporting cells. They also observed that Jagged2-- a binding molecule -- is expressed by progenitor hair cells of normal mice, while Notch1 -- a transmembrane receptor -- is expressed by the supporting cells.

As reported in Nature Genetics, these observations suggest that in the normal mouse, the Notch1 receptor acts through the supporting cell and inhibits inner-ear hair cell development by binding to Jagged2. The absence of Jagged2 in The Jackson Laboratory knockout mouse reduces this process of "lateral inhibition," resulting in the development of an increased number of sensory hair cells.

"Our findings demonstrate that the Notch pathway plays a role in lateral inhibitory interactions in mammals," Dr. Kelley reports. "In addition, this study represents the first demonstration of a molecular pathway that regulates the number of progenitor cells that develop as hair cells, and suggests that the inhibition of hair cell development is a limiting process in the embryonic, and possibly adult, mammalian cochlea."

The research was supported by grants from the National Institutes of Health, the March of Dimes Birth Defects Foundation, the National Organization for Hearing Research, and by an institutional grant to The Jackson Laboratory from the National Cancer Institute. Co-authors on the Nature Genetics paper include Yu Lan and Rulang Jiang of The Jackson Laboratory, Pamela J. Lanford of the Georgetown University School of Medicine, and Claire Lindsell and Gerry Weinmaster of the University of California, Los Angeles.

*******************

The Jackson Laboratory, founded in 1929, is a world leader in mammalian genetics research. With approximately 900 employees, the nonprofit, independent facility has a three-fold mission: to conduct basic genetic and biomedical research, train present and future scientists, and provide genetic resources to researchers worldwide.

The research was supported by grants from the National Institutes of Health, the March of Dimes Birth Defects Foundation, the National Organization for Hearing Research, and by an institutional grant to The Jackson Laboratory from the National Cancer Institute. Co-authors on the Nature Genetics paper include Yu Lan and Rulang Jiang of The Jackson Laboratory, Pamela J. Lanford of the Georgetown University School of Medicine, and Claire Lindsell and Gerry Weinmaster of the University of California, Los Angeles.

*******************

The Jackson Laboratory, founded in 1929, is a world leader in mammalian genetics research. With approximately 900 employees, the nonprofit, independent facility has a three-fold mission: to conduct basic genetic and biomedical research, train present and future scientists, and provide genetic resources to researchers worldwide.