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Suzanne L. Mansour, Ph.D.
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| Contribution
to Society
We anticipate that some of the genes we identify will help us to understand how the ear’s numerous cells, including the critical sensory hair cells, develop. Understanding and identifying these genes will make it possible to investigate the origins of human inner ear abnormalities and, potentially, to ameliorate hearing loss. Research Summary Congenital deafness with a genetic origin affects approximately 1 in 2000 children born every year. Studies of the origins of genetic deafness, and potential treatments, would be greatly facilitated by the development of mouse models of human deafness. The inner ear, which mediates the sensations of both hearing and balance, is derived almost entirely from a small patch of ectodermal cells, termed the otic placode, which is specified for an otic fate early in fetal development. Through a series of signaling interactions with the adjacent hindbrain and underlying mesenchyme, the otic ectoderm undergoes complex processes of morphogenesis and differentiation to arrive at its final functional form. Abnormalities of any of these processes lead to congenital deafness. To better understand these disorders, my laboratory has taken genetic and molecular approaches to identify and characterize genes that are important for the development and/or function of the mouse inner ear. Our current focus is on the requirements for and regulation of Fibroblast Growth Factor (FGF) signaling, which plays critical dosage-sensitive roles in the early development of the ear. Disruption of either Fgf3 or Fgf10 leads to variable defects of mouse inner ear morphogenesis. 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. More recent studies have uncovered a similar redundancy between Fgf3 and Fgf8. Our finding that Fgf8 induces Fgf10 expression provide an explanation for the similarities between the two double mutant phenotype and led us to propose a two-step FGF signaling cascade to initiate otic development. We have now characterized the expression patterns of all genes encoding FGFs and their receptors during the early phases of normal otic development. Our expression data also implicate Fgf4 and Fgf16 in ear development. We plan to test the requirements for these Fgf genes in inner ear development by generating and analyzing different mutant combinations. FGF signals activate a variety of intracellular signaling pathways, including the MAPK (mitogen-activated protein kinase) pathway. Our studies of gene expression during ear development identified Dusp6, which encodes a dual-specificity protein phosphatase specific for ERK (extracellular signal-regulated kinase) MAPK. DUSP6 dephosphorylates ERK, thus rendering it inactive. 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. By analogy with Drosophila puckered, which encodes a dual-specificity phosphatase that is a transcriptional target of signaling through the JNK (c-Jun N-terminal kinase) MAPK pathway, and which functions as a negative regulator of the JNK pathway by dephosphorylating JNK, we propose that Dusp6 may be a transcriptional target of the ERK pathway and that DUSP6 protein may feed back to regulate signaling through the ERK pathway. In support of this idea we find that Dusp6 expression is dependent on signaling through FGF receptors 1 and 2. Furthermore, genetic ablation of Dusp6 causes 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 are in progress. Publications Mansour SL and Schoenwolf GC (2005) Morphogenesis of the inner ear. In Springer Handbook of Auditory Research, D. Wu and M. Kelley, eds. (Springer-Verlag) In press. Ladher RK, Wright TJ, Moon AM, Mansour SL and Schoenwolf GC (2005 FGF8 initiates inner ear induction in chick and mouse. Genes Dev. 19:603-613 Wright TJ, Ladher R, McWhirter J, Schoenwolf GC, and Mansour SL (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 TJ and Mansour SL (2003) FGF signaling in ear development and innervation. Curr. Top. Dev. Biol. 57: 225-259 Wright TJ, Hatch E, Karabagli P, Karabagli H, Schoenwolf GC and Mansour SL (2003) Expression of mouse fibroblast growth factors and receptors during early inner ear development. Dev. Dyn. 228:267-272 Wright TJ and Mansour SL (2003) Fgf3 and Fgf10 are required for mouse otic placode induction. Development 130:3379-3390 Yang W, Li C and Mansour SL (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 SL (2000) Altered trafficking of organellar membrane proteins in Ap3b1 -deficient cells. J. Cell Sci. 113:4077-4086 Yang W and Mansour SL (1999) Expression and genetic analysis of prtb , a gene that encodes a highly conserved proline-rich protein expressed in the brain. Dev. Dyn. 215:108-116 Yang W, Musci TS, and Mansour SL (1997) Trapping genes expressed in the developing mouse inner ear. Hear. Res. 114:53-61 Mansour SL, Goddard JM, and Capecchi MR (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 Mansour SL (1990) Gene targeting in murine embryonic stem cells: Introduction of specific alterations into the mammalian genome. GATA 7:219-227 Mansour SL, Thomas KR, Deng C, and Capecchi MR (1990) Introduction of a lacZ reporter gene into the mouse int-2 locus by homologous recombination. Proc. Natl. Acad. Sci. USA 87:7688-7692 Mansour SL, Thomas KR, and Capecchi MR (1988) Disruption of the proto-oncogene int-2 in mouse embryo-derived stem cells: A general strategy for targeting mutations to nonselectable genes. Nature 336: 348-352 |
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