email: suzi.mansour@genetics.utah.edu

Associate Professor of Human Genetics Molecular Neuroscience Developmental Neuroscience Neurobiology of Disease Cellular Neuroscience

A.B. 1980, Harvard and Radcliffe Colleges; Ph.D. 1985, University of California, Berkeley; Postdoctoral Fellow, 1986-87 University of California, San Francisco; Postdoctoral Fellow, 1987-1993 University of Utah.

The mouse inner ear and dysmorphogenesis in an Fgf3 mutant. (A) An E15.5 mouse embryo was cleared and its inner ear filled with latex paint (brightfield). (B) Normal inner ear morphogenesis at E15.5 (darkfield). (C) Abnormal inner ear morphogenesis at E15.5 in an Fgf3 null mutant (darkfield).

RESEARCH:

FGF signaling and ear development

The inner ear, which mediates the sensations of hearing and balance, is derived from a small patch of ectodermal cells that are specified for an otic fate early in fetal development. Through a series of tissue interactions, 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 the early development of the ear. Disruption of either Fgf3 or Fgf10 leads to variable defects of mouse inner ear morphogenesis (Fig. 1) and our studies show that Fgf3 plays a critical role in sustaining dorsal otic gene expression (E. Hatch et al., submitted). In addition, we found that Fgf3/Fgf10 double mutants have no ear development at all, suggesting that these genes are required redundantly for the initial induction of the otic placode as well as individually in subsequent morphogenetic steps. Fgf3/Fgf8 double mutants have a similar phenotype because Fgf8 is upstream of Fgf10. We are now using conditional mutants to dissect the tissue origins of these inductive FGF signals and to prepare control and FGF-deficient otic placodes for microarray analyses. In addition, we characterized the expression patterns of all Fgf and Fgf receptor genes during the early phases of normal otic development. These data implicate Fgf4 and Fgf16 in ear development. Their roles are being determined through generation and analysis of different mutant combinations.

FGF signals activate several intracellular signaling pathways, including the MAPK pathway. Our studies of gene expression during ear development identified Dusp6, which encodes a dual-specificity protein phosphatase specific for ERK MAPK. DUSP6 dephosphorylates (inactivates) ERK. Dusp6 shares expression sites during embryogenesis with a variety of Fgf and Fgf receptor genes. In particular, Dusp6 is expressed in the mesenchyme surrounding the developing inner ear. This tissue gives rise to the bony capsule surrounding the inner ear, the bones of the middle ear and participates in reciprocal signaling with the inner ear epithelium. Molecular and genetic studies showed that Dusp6 is a transcriptional target of the ERK pathway and that DUSP6 protein feeds back to regulate signaling through the ERK pathway. Thus, Dusp6 mutants have dominant, incompletely penetrant phenotypes including short stature, craniosynostosis and otic capsule and middle ear dysplasias, similar to those found in humans and mice with activating mutations in FGF receptors. Studies of Dusp6 and related genes as well as mouse models of FGFR activating syndromes are in progress.

Selected Publications

Hatch, H.A., Urness, L.D., and Mansour, S.L. (2008) Fgf16IRESCre mice: A tool to inactivate genes expressed in inner ear cristae and spiral prominence epithelium. In revision.

Urness, L.D., Li, C., Wang, X., and Mansour, S.L. (2008) Expression of ERK signaling inhibitors Dusp6, Dusp7 and Dusp9 during mouse ear development. Dev. Dyn., 237: 163-169.

Hatch, E., Noyes, C.A., Wang, X., Wright, T.J., and Mansour, S.L. (2007) Fgf3 is required for dorsal patterning and morphogenesis of the inner ear. Development, 134:3615-3625.

Li, C., Scott, D.A., Hatch, E., Tian, X., and Mansour, S.L. (2007) Dusp6 is a negative feedback regulator of FGF stimulated ERK signaling during mouse development. Development, 134:167-176.

Mansour, S.L. and Schoenwolf, G.C. (2005) Morphogenesis of the inner ear. In: The Springer Handbook of Auditory Research. Vol. 26, Development of the Inner Ear. Kelley, M.W. Wu, D.K., Popper, A.N., Fay, R.R., eds. (Springer, New York), pp. 43-84.

Ladher, R.K., Wright, T.J., Moon, A.M., Mansour, S.L., and Schoenwolf, G.C. (2005) FGF8 initiates inner ear induction. Genes Dev., 19:603-613.

Wright, T.J., Ladher, R., McWhirter, J., Murre, C., Schoenwolf, G.C., and Mansour, S.L. (2004) Mouse FGF15 is the ortholog of human and chick FGF19, but is not uniquely required for otic induction. Dev. Biol., 269:264-275.

Wright, T.J., and Mansour, S.L. (2003) FGF signaling in ear development and innervation. Curr. Top. Dev. Biol., 57:225-59.

Wright, T.J., Hatch, E., Karabagli, P., Karabagli, H., Schoenwolf, G.C., and Mansour, S.L. (2003) Expression of mouse fibroblast growth factors and receptors during early inner ear development. Dev. Dyn., 228:267-272

Wright, T.J., and Mansour, S.L. (2003) Fgf3 and Fgf10 are required for mouse otic placode induction. Development, 130:3379-3390.

Yang, W., Li, C., and Mansour, S.L. (2001) Impaired motor coordination in mice that lack punc. Mol. Cell Biol., 21:6031-6043.

Yang, W., Li, C., Ward, D., Kaplan, J., and Mansour, S.L. (2000) Altered trafficking of organellar membrane proteins in Ap3b1-deficient cells. J. Cell Sci., 113:4077-4086.

Yang, W., Musci, T.S., and Mansour, S.L. (1997) Trapping genes expressed in the developing mouse inner ear. Hear. Res., 114:53-61.

Mansour, S.L., Goddard, J.M., and Capecchi, M.R. (1993) Mice homozygous for a targeted disruption of the proto-oncogene int-2 have developmental defects in the tail and inner ear. Development, 117:13-28.

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