Suzi Mansour's website
Suzi Mansour's PubMed Literature Search
The inner ear, which mediates the sensations of hearing and balance, is derived almost entirely from a small patch of ectodermal cells that are 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 the early development of the ear. Disruption of either Fgf3 or Fgf10 leads to variable defects of mouse inner ear morphogenesis and our studies show that Fgf3 plays a critical role in sustaining dorsal otic gene expression. In addition, we found that Fgf3/Fgf10 double mutants have no ear development at all, showing 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 using 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 (Urness et al., 2010).
Several interesting candidates for roles in otic induction and subsequent inner ear development are under further investigation. Finally, 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 (Li et al., 2007). Studies of Dusp6 and related genes are in progress.
Finally, one of our ongoing studies of FGF receptor gain-of-function models involves mice that carry the identical (overactive) FGF receptor mutation found in Muenke syndrome patients, who have craniosynostosis and hearing loss caused by one of the most frequent mutations in the human genome. These studies show that hearing loss in the Muenke syndrome model is predominantly low frequency and can occur with or without other symptoms, suggesting that unrecognized occurrences of the mutation might be responsible for isolated cases of low frequency hearing loss in humans (Mansour et al., 2009). Current studies of this model are aimed at determining the FGF ligand responsible for activating the Muenke mutant receptor and at chemical modification of FGF signaling in our mouse models to assess possibilities for hearing loss therapy.
(A) An E15.5 mouse embryo was cleared and its inner ear filled with latex paint. (B) Section taken through and E18.5 mouse cochlear duct showing expression of Dusp6 (purple).