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A mutation in the Lunatic fringe gene suppresses the effects of a Jagged2 mutation on inner hair cell development in the cochlea

2000; Elsevier BV; Volume: 10; Issue: 11 Linguagem: Inglês

10.1016/s0960-9822(00)00522-4

1879-0445

Nian Zhang, Gregory V. Martin, Matthew W. Kelley, Thomas Gridley,

Congenital heart defects research

Recent studies have demonstrated that the Notch signaling pathway regulates the differentiation of sensory hair cells in the vertebrate inner ear [1Adam J. Myat A. Le Roux I. Eddison M. Henrique D. Ish-Horowicz D. Lewis J. Cell fate choices and the expression of Notch, Delta and Serrate homologues in the chick inner ear: parallels with Drosophila sense-organ development.Development. 1998; 125: 4645-4654PubMed Google Scholar, 2Haddon C. Jiang Y.-J. Smithers L. Lewis J. Delta-Notch signalling and the patterning of sensory cell differentiation in the zebrafish ear: evidence from the mind bomb mutant.Development. 1998; 125: 4637-4644Crossref PubMed Google Scholar, 3Stone J.S. Rubel E.W. Delta1 expression during avian hair cell regeneration.Development. 1999; 126: 961-973PubMed Google Scholar, 4Bermingham N.A. Hassan B.A. Price S.D. Vollrath M.A. Ben-Arie N. Eatock R.A. et al.Math1: an essential gene for the generation of inner ear hair cells.Science. 1999; 284: 1837-1841Crossref PubMed Scopus (820) Google Scholar, 5Riley B.B. Chiang M.-.Y. Farmer L. Heck R. The deltaA gene of zebrafish mediates lateral inhibition of hair cells in the inner ear and is regulated by pax2.1.Development. 1999; 126: 5669-5678PubMed Google Scholar, 6Morrison A. Hodgetts C. Gossler A. Hrabé de Angelis M. Lewis J. Expression of Delta1 and Serrate1 (Jagged1) in the mouse inner ear.Mech Dev. 1999; 84: 169-172Crossref PubMed Scopus (160) Google Scholar, 7Lanford P.J. Lan Y. Jiang R. Lindsell C. Weinmaster G. Gridley T. Kelley M.W. Notch signalling pathway mediates hair cell development in mammalian cochlea.Nature Genet. 1999; 21: 289-292Crossref PubMed Scopus (374) Google Scholar, 8Shailam R. Lanford P.J. Dolinsky C.M. Norton C.R. Gridley T. Kelley M.W. Expression of proneural and neurogenic genes in the embryonic mammalian vestibular system.J Neurocytol in press. 2000; Google Scholar, 9Lanford P.J. Shailam R. Norton C.R. Gridley T. Kelley M.W. Expression of Math1 and Hes5 in the cochlea of wildtype and Jag2 mutant mice.J Assoc Res Otolaryngol. 2000; (in press)PubMed Google Scholar]. We have shown previously that in mice homozygous for a targeted null mutation of the Jagged2 (Jag2) gene, which encodes a Notch ligand, supernumerary hair cells differentiate in the cochlea of the inner ear [7Lanford P.J. Lan Y. Jiang R. Lindsell C. Weinmaster G. Gridley T. Kelley M.W. Notch signalling pathway mediates hair cell development in mammalian cochlea.Nature Genet. 1999; 21: 289-292Crossref PubMed Scopus (374) Google Scholar]. Other components of the Notch pathway, including the Lunatic fringe (Lfng) gene, are also expressed during differentiation of the inner ear in mice [6Morrison A. Hodgetts C. Gossler A. Hrabé de Angelis M. Lewis J. Expression of Delta1 and Serrate1 (Jagged1) in the mouse inner ear.Mech Dev. 1999; 84: 169-172Crossref PubMed Scopus (160) Google Scholar, 7Lanford P.J. Lan Y. Jiang R. Lindsell C. Weinmaster G. Gridley T. Kelley M.W. Notch signalling pathway mediates hair cell development in mammalian cochlea.Nature Genet. 1999; 21: 289-292Crossref PubMed Scopus (374) Google Scholar, 8Shailam R. Lanford P.J. Dolinsky C.M. Norton C.R. Gridley T. Kelley M.W. Expression of proneural and neurogenic genes in the embryonic mammalian vestibular system.J Neurocytol in press. 2000; Google Scholar, 9Lanford P.J. Shailam R. Norton C.R. Gridley T. Kelley M.W. Expression of Math1 and Hes5 in the cochlea of wildtype and Jag2 mutant mice.J Assoc Res Otolaryngol. 2000; (in press)PubMed Google Scholar, 10Morsli H. Choo D. Ryan A. Johnson R. Wu D.K. Development of the mouse inner ear and origin of its sensory organs.J Neurosci. 1998; 18: 3327-3335Crossref PubMed Google Scholar]. In contrast to the Jag2 gene, which is expressed in hair cells, the Lfng gene is expressed in non-sensory supporting cells in the mouse cochlea [10Morsli H. Choo D. Ryan A. Johnson R. Wu D.K. Development of the mouse inner ear and origin of its sensory organs.J Neurosci. 1998; 18: 3327-3335Crossref PubMed Google Scholar]. Here we demonstrate that a mutation in the Lfng gene partially suppresses the effects of the Jag2 mutation on hair cell development. In mice homozygous for targeted mutations of both Jag2 and Lfng, the generation of supernumerary hair cells in the inner hair cell row is suppressed, while supernumerary hair cells in the outer hair cell rows are unaffected. We also demonstrate that supernumerary hair cells are generated in mice heterozygous for a Notch1 mutation. We suggest a model for the action of the Notch signaling pathway in regulating hair cell differentiation in the cochlear sensory epithelium.