NIH Research Festival
Hgf encodes the multifunctional cytokine hepatocyte growth factor (HGF), which is secreted by mesenchymal cells and recognized by the tyrosine kinase receptor MET, expressed by epithelial cells. HGF is critical for cell signaling, cell motility, growth, and development. Noncoding mutations of HGF are associated with nonsyndromic hearing loss (DFNB39) in humans (Schultz et al, 2009). There are multiple isoforms of HGF whose expression, we hypothesize, are influenced by the DFNB39 noncoding mutations of HGF. We have created a mouse model which recapitulates a 10-bp intronic deletion found in some human DFNB39 patients. The 10 base pair deletion is located in intron 5 and founder lines retain a neomycin selection cassette, also located in intron 5 (Hgf^tmdel10Neo). A comprehensive phenotypic assessment shows no obvious defects in Hgf^tmdel10Neo/del10Neo mice other than cochlear abnormalities. Hearing loss was confirmed by ABR and DPOAE analyses. Hgf^tmdel10Neo/del10Neo mice show severe-to-profound hearing loss, while heterozygotes Hgf^tmdel10Neo/+ show normal hearing. The hearing phenotype is changed when the Neomycin cassette is removed by crossing to a ubiquitously expressing Cre-recombinase line (Hgf^tmdel10-). Hgf^tmdel10-/del10- mice show only mild-to-moderate hearing loss. Moreover, unlike their Hgf^tmdel10-/+ and Hgf^+/+ littermates, Hgf^tmdel10-/del10- mice are resistant to noise-induced hearing loss. A full elucidiation of the HGF isoforms, and their relative abundances, produced from Hgf^tmdel10Neo and Hgf^tmdel10- alleles will further our understanding of the essential functions of HGF in the human and mouse auditory system.
Scientific Focus Area: Genetics and Genomics
This page was last updated on Friday, March 26, 2021