SUZANNE L MANSOUR portrait
  • Adjunct Professor, Neurobiology Labs
  • Professor, Human Genetics
801-585-6893

Research Statement

The inner ear, which mediates the sensations of hearing and balance, is derived almost entirely from the otic placode, a small patch of ectodermal cells that is specified for an otic fate early in fetal development. Through a series of tissue interactions that are mediated by secreted signaling molecules, otic cells undertake complex processes of morphogenesis and differentiation to achieve their final functional form. Abnormalities of these processes lead to congenital deafness, which is the most common human sensory disorder. To better understand these disorders, my laboratory employs genetic and molecular approaches to identify and characterize genes that are important for the development and/or function of the mouse inner ear.

Fibroblast growth factor (FGF) signaling plays critical roles in early inner ear development. Disruption of either Fgf3 or Fgf10, which encode ligands that signal through the same FGF receptor isoforms, FGFR1b and FGFR2b, leads to defects of mouse inner ear morphogenesis. Fgf3 is required from the adjacent hindbrain to direct dorsal otic gene expression and induction of the endolymphatic duct. Fgf3 null mutants develop cystic inner ears and exhibit both hearing and vestibular dysfunction. Fgf10 is required for both posterior semicircular canal development and differentiation of cochlear non-sensory tissues that would undoubtedly cause hearing and balance dysfunction if the mice survived. Fgf3/Fgf10 double null mutants have no ear development at all, showing that these genes are required redundantly for the initial induction of the otic placode. We used conditional mutants to dissect the tissue origins of these inductive FGF signals. In addition, microarray comparisons of control and FGF-deficient otic placodes revealed transcriptional targets of FGF signaling that are required for subsequent development of the inner ear.

Inactivation of Fgf3 and Fgf10 alleles specifically within the otic epithelium and induction of a ubiquitously secreted, dominant-negative (dn) form of FGFR2b, revealed dosage sensitive roles for these genes in directing otic neurogenesis as well as in both cochlear and vestibular morphogenesis. Differential RNA-seq analysis of dissected otic epithelium from control and dnFGFR2b embryos revealed novel up and down-regulated target genes that are the subject of current functional studies as potential hearing loss genes (Urness et al., 2018 BioRxiv 430876 preprint).    

Many forms of sensorineural hearing loss, whether caused by genetic or environmental factors, are characterized by loss of cochlear sensory cells, which do not regenerate in mammals. In contrast, birds and fish regenerate lost sensory cells from residual cochlear supporting cells. Strategies for hearing restoration in mammals are focused on manipulating developmental signals to change cochlear supporting cell identity. We showed that mice with an activating mutation in FGFR3 that models Muenke syndrome have hearing loss associated with an identity switch between two types of supporting cells. Muenke syndrome model mice also have ectopic sensory cells. We found that supporting cell identity and hearing are restored in these FGFR3 mutants by genetically reducing the level of FGF10, a ligand does not normally activate FGFR3. Interestingly, the ectopic sensory cells remain. We went on to show that the Muenke syndrome mutation changes FGFR3 specificity so that it becomes responsive to FGF10. Most remarkably, we found that the supporting cell fate switch is actually completed the “rescued” animals, but is then gradually reversed. This shows that seemingly fully differentiated cochlear supporting cells can reversibly switch fates in an FGF-dependent manner. Since some immature supporting cells can be induced under certain circumstances to convert to sensory cells, this FGF-dependent plasticity is being investigated so that it can be exploited as a component of strategies designed to promote mammalian sensory cell regeneration from supporting cells.

Research Keywords

  • Hearing
  • Deafness
  • Mouse Models
  • Inner Ear
  • Genetics
  • Developmental Biology
  • Embryo and Fetal Development
  • Gene Expression Regulation, Developmental
  • Growth and Embryonic Development

Presentations

  • Wright, T.J. and Mansour, S.L. The roles of mouse fibroblast growth factors (Fgf)3 and Fgf8 in inner ear development. 27th Association for Research in Otolaryngology Winter Meeting, Daytona Beach, FL (PLATFORM). , , 2004.
  • Ladher, R.K., Wright, T.J., Mansour, S.L., and Schoenwolf, G.C. Initiating inner ear induction: A role for endodermal FGF-8 in chick otic developoment. Molecular Biology of Hearing and Deafness, UCSD School of Medicine, Division of Otolaryngology, Bethesda MD. , , 2004.
  • Hatch, E.P., Wright, T.J., and Mansour, S.L. The roles of mouse Fgf4, Fgf8, and Fgf16 during early inner ear development. Molecular Biology of Hearing and Deafness, UCSD School of Medicine, Division of Otolaryngology, Bethesda MD. , , 2004.
  • Hatch, E., Wright, T.J., Karabagli, H., Karabagli, P., Ladher, R., Schoenwolf, G.D., Mansour, S.L., "The roles of mouse Fgfs and Fgfrs during early in inner ear development," Society for Developmental Biology Southwest/Gulf Regional Meeting, Salt Lake City, UT. (PLATFORM). , , 2003.
  • Wright, T. J. and Mansour, S.L. (2002) Fgf-3 and Fgf-10 in mouse inner ear development. 25th Association for Research in Otolaryngology Winter Meeting, St. Petersburg FL, January 27-31. (PLATFORM). , , 2002.
  • Wright, T.J. and Mansour, S.L. Fibroblast Growth Factors in Ear Development. Molecular Biology of Hearing and Deafness, Bethesda, MD (PLATFORM). , , 2001.
  • Wright, T.J. and Mansour, S.L. Fibroblast growth factors in ear development. 21st Association for Research in Otolaryngology Winter Meeting, St. Petersburg FL. (PLATFORM). , , 2001.
  • Wright, T.J. and Mansour, S.L. 59th Society for Developmental Biology National Meeting, Boulder CO, June(Tracy Wright, presenter). , , 2000.
  • Mansour, S. April 2-6, "Ear induction and patterning," EB2005 Mini-Symposium on Sensory Systems, FASEB, San Diego, CA. , , 2005.
  • Li, C. and Mansour, S.L., March 19-24, "FGF signaling and its regulation during the development of the mouse ear." 28th Association for Research in Otolaryngology Winter Meeting, New Orleans, LA. , , 2005.
  • Wright, T.J., Noyes, A., Wang, X., Li, C., and Mansour, S.L. September 30-October 3, "FGF signaling in mouse peripheral auditory system development." Molecular Biology of Hearing and Deafness, UCSD School of Medicine, Division of Otolaryngology, Bethesda, MD. , , 2004.
  • Mansour, S.L., Wright, T. J., Li, C., and Scott, D., September 19-21. "FGF signaling and its regulation during the development of the mouse ear." Society for Developmental Biology Southwest/Gulf Regional Meeting, Salt Lake City, UT. , , 2003.
  • Wright, T.J. and Mansour, S.L., February 22-27, "Fgfs in mouse inner ear development." 26th Association for Research in Otolaryngology Winter Meeting, Daytona Beach FL. , , 2003.
  • Wright, T.J. and Mansour, S.L. July 18-22. "Fibroblast growth factors in ear development," 60th Society for Developmental Biology National Meeting, Seattle WA. , , 2001.
  • Mansour, S., March 11-13. "A gene trap approach to inner ear development and function." Symposium on Development of Sensory Systems, 32nd Northwest Regional Developmental Biology Conference, Friday Harbor WA. , , 1999.
  • Yang, W., Li, C., Wang, X.-F., and Mansour, S.L., October 8-11, "Trapping genes involved in murine inner ear development." Molecular Biology of Hearing and Deafness, UCSD School of Medicine, Division of Otolaryngology, Bethesda MD. , , 1998.
  • Carpenter, E., Mansour, S., Condie, B., and Landry, C. January 24-31, "Nervous System Development: A Genetic Viewpoint." 31st Winter Conference on Brain Research, Snowbird UT. , , 1998.
  • Mansour S; Musci T; Yang W. "A gene-trap screen to identify genes involved in inner ear development." Molecular Biology of Hearing and Deafness, UCSD School of Medicine, Division of Otolaryngology, Bethesda MD. , , 1995.
  • Mansour SL. "The role of Fgf3 in the development of the inner ear." Workshop in Mouse Molecular Neurogenetics, The Jackson Laboratory, Bar Harbor ME. , , 1994.
  • Mansour SL. "Targeted disruption fo int-2 (fgf-3)causes developmental defects in th etail and inner ear." 8th MCDB/ISU Symposium, Ames IA. , , 1993.
  • Hatch EP, Mansour SL, Wright TJ. The roles of mouse Fgf4, Fgf8 and Fgf16 during early inner ear development. Poster session presented at 63rd Society for Developomental Biology National Meeting, Calgary, Alberta. Poster, Presented, 2004.
  • Wright TJ, Mansour SL. The roles of mouse fibroblast growth factors (Fgf)3 and Fgf8 in inner ear development. Poster session presented at 27th Association for Research in Otolaryngology Winter Meeting, Daytona Beach, FL. Poster, Presented, 2004.
  • Hatch EP, Wright TJ, Mansour SL. The roles of mouse Fgf4, Fgf8 and Fgf16 during early inner ear development. Poster session presented at Molecular Biology of Hearing and Deafness, UCSD School of Medicine, Division of Otolaryngology, Bethesda, MD. Poster, Presented, 2004.
  • Li C, Scott D, Mansour SL. FGF signaling and its regulation during the development of the mouse ear. Poster session presented at 27th Association for Research in Otolaryngology Winter Meeting., Daytona Beach, FL. Poster, Presented, 2004.
  • Wright TJ, Noyes A, Wang X, Li C, Mansour SL. FGF signaling in mouse peripheral auditory system development. Poster session presented at Molecular Biology of Hearing and Deafness, UCSD School of Medicine, Division of Otolaryngology, Bethesda, MD. Poster, Presented, 2004.
  • Ladher RK, Wright TJ, Mansour SL, Schoenwolf GC. Initiating inner ear induction: A role for endodermal Fgf-8 in chick otic development. Poster session presented at Molecular Biology of Hearing and Deafness, UCSD School of Medicine, Division of Otolaryngology, Bethesda, MD. Poster, Presented, 2004.
  • Wright TJ, Mansour SL. Fgf3 and Fgf8 are required redundantly for mouse otic induction. Poster session presented at 63rd Society for Developmental Biology National Meeting, Calgary, Alberta. Poster, Presented, 2004.
  • Hatch E, Wright TJ, Karabagli H, Karabagli P, Ladher R, Schoenwolf GD, Mansour SL. The roles of mouse Fgfs and Fgfrs during early inner ear development. Poster session presented at Society fro Developmental Biology Southwest/Gulf Regional Meeting, Salt Lake City, UT. Poster, Presented, 2003.
  • Li C, and Mansour SL. Dusp6 is a negative regulator of FGF signaling. Poster session presented at 62nd Society for Developmental Biology National Meeting, Boston, MA. Poster, Presented, 2003.
  • Wright TJ, Hatch E, Karabagli H, Karabagli P, Ladher R, Schoenwolf GC, Mansour SL. The roles of mouse Fgfs and Fgfrs during early inner ear development. Poster session presented at 62nd Society for Developmental Biology National Meeting,, Boston, MA. Poster, Presented, 2003.
  • Wright TJ, Mansour SL. Fibroblast growth factors -3, -8, and -10 in inner ear development. Poster session presented at 61st Society for Developmental Biology National Meeting, Madison, WI. Poster, Presented, 2002.
  • Wright TJ, Mansour SL. Fgf-3 and Fgf-10 in mouse inner ear development. Poster session presented at American Society for Human Genetics Annual Meeting, Washington, DC. Poster, Presented, 2002.
  • Wright TJ, Mansour SL. Fgf-3 and Fgf-10 in mouse inner ear development. Poster session presented at 25th Association for Research in Otolaryngology Winter Meeting, St. Petersburg, FL. Poster, Presented, 2002.
  • Francis L, and Mansour SL. Role of Nope and Dcc in otic development. Poster session presented at 61st Society for Developmental Biology National Meeting, Madison, WI. Poster, Presented, 2002.
  • Wright TJ, Mansour SL. Fibroblast Growth Factors in Ear Development. Poster session presented at 21st Association for Research in Otolaryngology Winer Meeting, St. Petersburg, FL. Poster, Presented, 2001.
  • Wright TJ, Mansour SL. Fibroblast Growth Factors in Ear Development. Poster session presented at Molecular Biology of Hearing and Deafness, Bethesda, MD. Poster, Presented, 2001.
  • Wright TJ, Mansour SL. 59th Society for Developmental Biology National Meeting. Boulder, CO. Poster, Presented, 2000.
  • Yang W, Musci T, Mansour SL. Trapping Genes Involved in Inner Ear Development. Poster session presented at 57th Society for Developmental Biology National Meeting, Stanford, CA. Poster, Presented, 1998.
  • Mansour SL, Musci T, Yang W. Trapping Genes Involved in Inner Ear Development. Snowbird, UT. Poster, Presented, 1997.
  • Yang W, Musci T, Mansour SL. A Screen to Identify Genes Involved in Inner Ear Development. Cold Spring Harbor. Poster, Presented, 1996.

Languages

  • English, Fluent.

Publications

  • Mansour, S.L., Li, C. and Urness, L.D (date unknown). Genetic rescue of Muenke syndrome model hearing loss reveals prolonged FGF-dependent plasticity in cochlear supporting cell fates. Vol. 27, 2320-2331. Accepted, .
  • Hatch EP, Noyes CA, Wang X, Wright TJ, Mansour SL (date unknown). Fgf3 is required for dorsal patterning and morphogenesis of the inner ear epithelium. Vol. 134, 3615-25. Accepted, .
  • Wright TJ, Mansour SL (date unknown). Fgf3 and Fgf10 are required for mouse otic placode induction. Vol. 130, 3379-90. Accepted, .
  • Quadros, R.M., Miura, H., Harms, D.W., Akatsuka, H., Sato, T., Aida, T., Redder, R., Richardson, G.P., Inagaki, Y., Sakai, D., Buckley, S.M., Seshacharyulu, P., Batra, S.K., Behlke, M.A., Zeiner, S.A., Jacobi, A.M., Izu, Y., Thoreson, W.B., Urness, L.D., Mansour, S.L., Ohtsuka, M., Gurumurthy, C.B. (date unknown). Easi-CRISPR: a robust method for one-step generation of mice carrying conditional and insertion alleles using long ssDNA donors and CRISPR ribonucleoproteins. Vol. 18, 92. Accepted, .
  • Urness LD, Paxton CN, Wang X, Schoenwolf GC, Mansour SL (date unknown). FGF signaling regulates otic placode induction and refinement by controlling both ectodermal target genes and hindbrain Wnt8a. Vol. 340, 595-604. Accepted, .
  • Ladher RK, Wright TJ, Moon AM, Mansour SL, Schoenwolf GC (date unknown). FGF8 initiates inner ear induction in chick and mouse. Vol. 19, 603-13. Accepted, .
  • Urness, L.D., Wang, X., Shibata, S., Ohyama, T. and Mansour, S.L. (date unknown). Fgf10 is required for specification of non-sensory regions of the cochlear epithelium. Vol. 400, 59-71. Accepted, .
  • Mansour SL, Twigg SR, Freeland RM, Wall SA, Li C, Wilkie AO (date unknown). Hearing loss in a mouse model of Muenke syndrome. Vol. 18, 43-50. Accepted, .