My lab is interested in understanding the genetic mechanisms underpinning the normal development and function of the ear, which mediates the sensations of hearing and balance. Dysfunction of the ear is a common congenital condition, affecting approximately 1 in 300 births, and many individuals born with normal hearing will subsequently develop age-related hearing loss caused by irreparable damage to auditory sensory cells. Our particular focus is on the roles and regulation of the genes coding for Fibroblast Growth Factor (FGF) signaling components in mouse ear development. These signals control many different aspects of ear development, including the initial induction, specification and shaping of the ear primoridium, as well as later processes of sensory and supporting cell differentiation. Indeed, mutations in FGF signaling components lead to hearing impairment in both mice and humans. Our mouse models of these conditions can help in devising therapeutic strategies.
A second focus of our research, which arose from studies of ear development in mice bearing mutations in Fgf3 and Fgf10, is heart development. Normal heart development is a complex process involving communication and coordination between cells that are located in different areas of the developing fetus. Congenital heart defects occur in approximately 1% of all births and many of the most common abnormalities are seen in mice with genetically engineered disturbances of FGF signaling pathways. We are determining exactly where specific FGFs are located, how these sites relate to cells that receive the signals, as well as exactly how, when, and where these signaling events affect cardiovascular development. Since the FGF signaling system is a potential drug target, developing an understanding of the details of the timing and quantitative nature of its contributions to cardiovascular development will be vital in devising effective therapies.
My lab is interested in understanding the genetic mechanisms responsible for the normal development and function of the ear, which mediates our sensations of hearing and balance. Dysfunction of the ear, either in isolation, or in conjunction with other symptoms, is one of the most common human birth disorders, affecting approximately 1 in 300 births. To put this in perspective, consider the facts that congenital hearing loss occurs three times more frequently than Down’s syndrome, six times more frequently than spina bifida and fifty times more frequently than phenylketonuria; conditions for which routine screening was established long before the advent of universal newborn hearing screens about 10-15 years ago. Even if we are born with perfectly normal hearing, most of us will experience high frequency hearing loss as we age, and by the age of 80, at least 50% of us will have clinically significant hearing loss and consequent difficulties with communication unless we take advantage of the new technologically advanced hearing aids.
At least 50% of newborn hearing loss is caused by gene mutations, and my lab focuses on understanding the roles and regulation of the genes coding for Fibroblast Growth Factor (FGF) signaling components in ear development using the mouse model system. We study FGF signaling because of its essential roles in virtually all aspects and stages of ear development. Thus, mutations in various FGF signaling components lead to deafness in both mice and humans. Our research showed that particular Fgf genes are required to initiate inner ear development and that these same genes are re-used later in development to give the inner ear its characteristic shape and allow it to function. Studies of mice bearing targeted mutations in these Fgf genes are helping us to understand the hearing loss that occurs in humans that carry mutations in the very same genes. In addition, one of our ongoing studies involves mice that carry the identical (overactive) FGF receptor mutation found in Muenke syndrome patients, who have skull malformations and hearing loss caused by one of the most frequent mutations in the human genome. These studies are showing that Muenke syndrome hearing loss 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. Some of our future studies will be aimed at modulating FGF signaling in our mouse models to assess possibilities for hearing loss therapy.
Moderate-to-severe heart defects requiring medical intervention affect about 6 to19 out of every 1000 births. Many of these defects are genetic in origin. Since the heart is the first organ to form and function during fetal development, many congenital heart defects have their origins very early in fetal life. Thus, to understand congenital heart disease and devise preventions and therapies we must learn how this organ develops and determine the identities and roles of the critical genes involved. There are several excellent model systems, including chicks, fish and mice, being used to study congenital heart disease at the University of Utah. My colleague, Dr. Anne Moon, was among the first investigators to show that a class of very potent signals, known as the Fibroblast Growth Factors (or FGFs), play critical roles in heart development. My lab has studied the roles of these signals in the development of the mouse inner ear, which like ours, is required for normal hearing and balance. In the course of these studies we happened to observe that a particular FGF (FGF3), which had not been previously implicated in heart development, works together with another FGF (FGF10) to provide signals that control not only ear development, but also cardiovascular development. When we inactivate these signals, using the gene targeting technology that Dr. Mario Capecchi won the Nobel Prize for last year, we see a variety of malformations that resemble some of the congenital malformations typical of patients with DiGeorge and CHARGE syndromes. We are using our recent AHA funding to investigate how FGF3 and FGF10 function together to direct normal heart development.
Normal heart development is a complex process involving communication and coordination between cells that are located in different areas of the developing fetus. We are determining exactly where the specific FGF signaling molecules we are interested in are coming from, how these sites relate to the cells that receive the signals, as well as exactly how, when, and where these signaling events affect cardiovascular development. As I mentioned this is accomplished using the mouse model system, which develops very similarly (but on a much smaller scale!) to humans and has all of the same FGF genes. We use techniques that specifically label cells that express the FGFs and their receptors at several early stages of cardiovascular development in normally developing mouse embryos. We also use mouse mutants generated by our group to determine the origins of the cardiovascular malformations that are caused when specific FGF genes are missing, and we will determine which of the many FGF signal locations are important for cardiovascular development. I expect that the results of this initial study will be published and provide the foundation for expanded grant proposals to the AHA and/or the NIH.
Many of the cardiovascular malformations we see in mutant mice lacking various components of the FGF signaling system are similar to the most common human cardiovascular birth defects. Thus it is possible that our studies could lead eventually to the discovery of specific human FGF gene mutations that cause cardiovascular disease. Even if such single gene mutations are rare, the findings would permit diagnosis in affected families. More broadly, we think that disturbances of FGF signaling caused by small changes in many genes may contribute in complex ways to cardiovascular birth defects. Since the FGF signaling system is a potential drug target, developing an understanding of the details of the timing and quantitative nature of its contributions to cardiovascular development will be vital in devising effective therapies.
References to Publications:
Urness, L.D., Wang, X., Shibata, S., Ohyama T. and Mansour S.L. (2015) Fgf10 is required for specification of non-sensory regions of the cochlear epithelium. Dev. Biol. 400:59-71.
Jackson A, Kasah S, Mansour SL, Morrow B, Basson MA. (2014) Endoderm-specific deletion of Tbx1 reveals an FGF-independent role for Tbx1 in pharyngeal apparatus morphogenesis. Dev Dyn. 2014 Sep;243(9):1143-51. doi: 10.1002/dvdy.24147. Epub 2014 Jun 12.
Mansour, S.L., Li, C. and Urness, L.D. (2013) Genetic rescue of Muenke syndrome model hearing loss reveals prolonged FGF-dependent plasticity in cochlear supporting cell fates. Genes Dev. 27: 2320-2331.
Urness L.D., Bleyl S.B., Wright T.J., Moon A.M. and Mansour S.L. (2011) Redundant and dosage sensitive requirements for Fgf3 and Fgf10 in cardiovascular development. Dev. Biol. 256: 383-397
Ohta, S., Mansour, S.L., and Schoenwolf, G.C. (2010) BMP/SMAD Signaling regulates the cell behaviors that drive the initial dorsal-specific regional morphogenesis of the otocyst. Dev. Biol. 347: 369-381. Featured on the cover.
Urness, L. D., Paxton, C., Wang, X., Schoenwolf, G. C., and, Mansour, S. L. (2010) FGF signaling regulates otic placode induction and refinement by controlling both ectodermal target genes and hindbrain Wnt8a. Dev. Biol. 340: 595-604.
Abler, L. L., Mansour S. L., and Sun, X. (2009) Conditional Gene Inactivation Reveals Roles for Fgf10 and Fgfr2 in Establishing a Normal Pattern of Epithelial Branching in the Mouse Lung. Dev. Dyn. 238: 43-50.
*#Mansour, S. L., *Twigg, S. R. F., Freeland, R. M., Wall, S. A., Li, C., and Wilkie, A. O. M. (2009) Hearing loss in a mouse model of Muenke syndrome. Hum. Mol. Genet. 18: 43-50. *indicates equal contribution. # indicates corresponding author.
Hatch E. P., Urness, L. D. and Mansour, S. L. (2009) Fgf16IRESCre mice: A tool to inactivate genes expressed in inner ear cristae and spiral prominence epithelium. Dev. Dyn. 238: 358-366.
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. P., 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 epithelium. 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.
*Ladher, R. K., *Wright, T. J., Moon, A. M., Mansour, S. L. and Schoenwolf, G. C. (2005) FGF8 initiates inner ear induction in chick and mouse. Genes Dev. 19: 603-613. *indicates equal contribution.
Satoh, Y., Haraguchi, R., Wright, T. J., Mansour, S. L., Partanen, J., Hajihosseini, M. K., Eswarakumar, V. P., Lonai, P. and Yamada, G. (2004) Regulation of external genitalia development by concerted actions of FGF ligands and FGF receptors. Anat. Embryol. 208: 479-486.
*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. *indicates equal contribution.
Wright, T. J., Hatch, E., Karabagli, H., Karabagli, P., Schoenwolf, G. C., and Mansour, S. L. (2003) Expression of mouse fibroblast growth factor and fibroblast growth factor receptor genes 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) Defective organellar membrane protein trafficking in Ap3b1-deficient cells. J. Cell Sci. 113: 4077-4086.
Yang, W. and Mansour, S. L. (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, 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.
Mansour, S. L., Thomas, K. R., Deng, C., and Capecchi, M. R. (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, S. L., Thomas, K. R., and Capecchi, M. R. (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.
Mansour, S. L. and Martin, G. R. (1988) Four classes of mRNA are expressed from the mouse int-2 gene, a member of the FGF gene family. EMBO J. 7: 2035-2041.
Mansour, S. L., Grodzicker, T., and Tjian, R. (1986) Downstream sequences affect transcription initiation from the adenovirus major late promoter. Mol. Cell. Biol. 6: 2684-2694.
Mansour, S. L., Grodzicker, T., & Tjian, R. (1985) An adenovirus vector system used to express polyoma virus tumor antigens. Proc. Natl. Acad. Sci. USA, 82: 1359-1363.
Suzanne Mansour, Ph.D.
Post Doc Members
Lisa Urness, Ph.D.
Former Lab Members
Jennifer Wei Yang
Tracy J. Wright
C. Albert Noyes
Department of Human Genetics
15 North 2030 East, Room 7110A
University of Utah
Salt Lake City, UT 84112-5330