Inner ear development
We have identified FGF20 as an essential signal that regulates the development of sensory receptors in the inner ear. Mice lacking FGF20 are viable, healthy and congenitally deaf. FGF20 expression also marks a progenitor cell lineage in the olfactory epithelium and functions to regulate the growth of the underlying nasal turbinates. Our aims are to identify the molecular mechanisms that regulate the expression of Fgf20 during embryonic development of the cochlea and olfactory epithelium; to determine how FGF20 regulates sensory progenitor cell growth and the differentiation of cochlear outer hair and supporting cells in the organ of Corti; and to identify the specific genes and pathways that act downstream of FGF20 during cochlear and olfactory development using Next Gen mRNA sequencing (TRAP-seq). We are testing the hypothesis that FGF signaling can enhance sensory cell regeneration following ototoxic damage.
Inner ear and FGF20 Publications
1. Hurle B, Ignatova E, Massironi SM, Mashimo T, Rios X, Thalmann I, . . . Ornitz DM (2003) Non-syndromic vestibular disorder with otoconial agenesis in tilted/mergulhador mice caused by mutations in otopetrin 1. Hum Mol Genet 12(7):777-789.
2. Hughes I, Blasiole B, Huss D, Warchol ME, Rath NP, Hurle B, . . . Ornitz DM (2004) Otopetrin 1 is required for otolith formation in the zebrafish Danio rerio. Dev Biol 276(2):391-402. PMCID: PMC2522322.
3. Hughes I, Saito M, Schlesinger PH & Ornitz DM (2007) Otopetrin1 activation by purinergic nucleotides regulates intracellular calcium. Proc Natl Acad Sci U S A 104(29):12023-12028. PMCID: PMCID: PMC1924595.
4. Hughes I, Binkley J, Hurle B, Green ED, NISC Comparative Sequencing Program, Sidow A & Ornitz DM (2008) Identification of the Otopetrin Domain, a conserved domain in vertebrate otopetrins and invertebrate otopetrin-like family members. BMC Evolutionary Biology 8:41.
5. Kim E, Hyrc KL, Speck J, Lundberg YW, Salles FT, Kachar B, . . . Ornitz DM (2010) Regulation of cellular calcium in vestibular supporting cells by Otopetrin 1. J. Neurophysiol. 104(6):3439-3450. PMCID: PMCID: PMC3007624.
6. Hurle B, Marques-Bonet T, Antonacci F, Hughes I, Ryan JF, Program NCS, . . . Green ED (2011) Lineage-specific evolution of the vertebrate Otopetrin gene family revealed by comparative genomic analyses. BMC Evol Biol 11:23. PMCID: PMC3038909.
7. Kim E, Hyrc KL, Speck J, Salles FT, Lundberg YW, Goldberg MP, . . . Ornitz DM (2011) Missense mutations in Otopetrin 1 affect subcellular localization and inhibition of purinergic signaling in vestibular supporting cells. Mol. Cell. Neurosci. 41(3):655-661. PMCID: PMCID: PMC3046300.
8. Barak H, Huh SH, Chen S, Jeanpierre C, Martinovic J, Parisot M, . . . Kopan R (2012) FGF9 and FGF20 maintain the stemness of nephron progenitors in mice and man. Dev Cell 22(6):1191-1207. PMCID: PMC3376351.
9. Haara O, Harjunmaa E, Lindfors PH, Huh SH, Fliniaux I, Aberg T, . . . Thesleff I (2012) Ectodysplasin regulates activator-inhibitor balance in murine tooth development through Fgf20 signaling. Development 139(17):3189-3199. PMCID: PMC3413164.
10. Huh SH, Jones J, Warchol ME & Ornitz DM (2012) Differentiation of the lateral compartment of the cochlea requires a temporally restricted FGF20 signal. PLoS Biol 10(1):e1001231. PMCID: PMC3250500.
11. Huh SH, Närhi K, Lindfors PH, Häärä O, Yang L, Ornitz DM & Mikkola ML (2013) Fgf20 governs formation of primary and secondary dermal condensations in developing hair follicles. Genes Dev. 27(4):450-458. PMCID: PMC3589561.
12. Huh SH, Warchol ME & Ornitz DM (2015) Cochlear progenitor number is controlled through mesenchymal FGF receptor signaling. Elife 4:1-17. PMCID: PMC4434254.