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Suzanne L. Mansour

Associate Professor of Human Genetics

A.B. Harvard University

Ph.D. University of California, Berkeley

Research

References

suzi.mansour@genetics.utah.edu

Suzi Mansour's PubMed Literature Search

Research

The inner ear, which mediates the sensations of hearing and balance, is derived almost entirely from a small patch of cranial ectoderm, termed the otic placode, which is specified for an otic fate early in fetal development.
Following a series of signaling interactions with several nearby tissues, the otic ectoderm undergoes complex processes of morphogenesis and differentiation to arrive at its 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 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 (Fig. 1) and our studies suggest 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, suggesting that these genes are required redundantly for the initial induction of the otic placode as well as individually in subsequent morphogenetic steps. A similar phenotype is seen in Fgf3/Fgf8 double mutants and this occurs because Fgf8 is upstream of Fgf10. We are now using conditional mutants to dissect the tissue origins of these inductive FGF signals and to compare control and FGF-deficient otic placodes via 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 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 (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 required for normal morphogenesis of both compartments. 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 are in progress.

Finally, FGF signaling can also be modulated at the level of the receptor. The heterozygous Pro250Arg substitution mutation in FGFR3, which increases ligand-dependent signaling, is the most common genetic cause of craniosynostosis in humans and defines Muenke syndrome. Since FGF signaling plays dosage sensitive roles in the differentiation of the auditory sensory epithelium, we evaluated hearing in a large group of Muenke syndrome subjects, as well as in the corresponding mouse model (Fgfr3P244R). The Muenke syndrome cohort showed significant, but incompletely penetrant, predominantly low-frequency sensorineural hearing loss, and the Fgfr3P244R mice showed dominant, fully penetrant hearing loss that was more severe than that of Muenke syndrome individuals, but had the same pattern of relative high-frequency sparing. The mouse hearing loss correlated with an alteration in the fate of supporting cells along the entire length of the cochlear duct, with the most extreme abnormalities found at the apical or low-frequency end. We conclude that low-frequency sensorineural hearing loss is a characteristic feature of Muenke syndrome, and that the genetically equivalent mouse provides an excellent model that could be useful in testing hearing loss therapies aimed at manipulating the levels of FGF signaling in the inner ear.

(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).

References