Regulation of sensory development and regeneration
2-3 infants per 1000 live births suffer from congenital hearing loss. In addition, age-related hearing loss affects one third of people over the age of 65 at the United States. In mammals, once damaged, the sensory epithelium at the organ of Corti has no capacity to regenerate resulting in irreversible hearing loss.
We have engineered mice that lack Fibroblast Growth Factor 20 (Fgf20). Fgf20 knockout mice (Fgf20-/-) have profound hearing loss but are otherwise healthy. The cellular organization within the organ of Corti of Fgf20-/- mice was severely disrupted and Fgf20-/- mice had significantly fewer outer hair cells and outer supporting cells than in Fgf20+/+ or Fgf20+/- mice.
Expression patterns and the Fgf20 knockout phenotype demonstrate that FGF20 is critical and essential regulator of cochlear development. Loss of Fgf20 expression in the adult mammalian inner ear and that FGF signaling is necessary for avian sensory epithelial regeneration provides one possible explanation for the inability of the mammalian inner ear to regenerate. In this project, we will identify cellular targets of FGF20 and explore possible mechanisms by which FGF20 can regulate cochlear development and sensory epithelial patterning. Understanding the mechanisms by which FGF20 regulates cochlear development and patterning will be essential to develop methods to therapeutically activate FGF20-regulated developmental programs in the adult.
We have also generated Fgf9 and Fgf20 compound mice which showed new phenotype-shortened cochlear length. We identified that FGF9 and FGF20 function redundantly to regulate cochlear sensory progenitor proliferation and the size of the cochlea. In addition, we identified that FGF9 and FGF20 send the signal to mesenchymal FGFR1 and FGFR2 to promote cochlear sensory progenitor proliferation.
Expression patterns and the Fgf9 and Fgf20 knockout phenotype demonstrate that Fgf9 and Fgf20 are critical and essential regulators of cochlear development. In this project, we will identify cellular targets of Fgf9 and Fgf20 and explore possible mechanisms by which Fgf9 and Fgf20 can regulate cochlear development and sensory epithelial patterning.
Regulation of kidney development and regeneration
End stage renal disease (ESRD) presents a growing health problem affecting the aging population for which only two forms of treatment exist: dialysis and kidney transplantation. ESRD occurs because aging depletes nephrons due to injury or cumulative environmental insults due to inability to regenerate new nephrons. Because of the absence of adult stem cells, the kidney has only a limited repair capacity.
We have recently identified that Fgf20 and Fgf9 are necessary and sufficient to maintain kidney progenitors in vivo and in vitro. Loss of FGF20 in humans, or both ligands in mice, results in completely penetrant kidney agenesis. In this project, we will identify cellular and molecular mechanisms by which Fgf9 and Fgf20 regulate nephron progenitor development and maintenance.