Sung-Ho Huh, PhD – Principal Investigator
DRC II 6036
UNMC, Omaha, NE 68198-5965
Dr. Sung-Ho Huh’s laboratory is interested in the organs development and regeneration using mice as model system. We are using molecular, genetic, biochemical and physiological approach to understand the role of the growth factor signaling including FGF signaling and Wnt signaling during organogenesis focusing in inner ear and kidney development. Using gene knockout and conditional knockout technology, we generated mutant mice which has defect in inner ear and kidney. By studying those mutants, we will identify molecules required for sensory and nephron development and maintenance. This information will be utilized to develop new therapies for hearing loss and kidney diseases.
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.
- Jansson L, Ebeid M, Shen JW, Mokhtari TE, Quiruz LA, Ornitz DM, Huh SH*, Cheng AG*. β-Catenin is required for radial cell patterning and identity in the developing mouse cochlea. Proc Natl Acad Sci U S A. 2019 Oct 15;116(42):21054-21060. doi: 10.1073/pnas.1910223116. *Correspondence
- Yang LM, Cheah KSE, Huh SH*, Ornitz DM*. Sox2 and FGF20 interact to regulate organ of Corti hair cell and supporting cell development in a spatially-graded manner. PLoS Genet. 2019 Jul;15(7):e1008254. doi: 10.1371/journal.pgen.1008254. *Correspondence
- Yang LM, Huh SH, Ornitz DM. FGF20-Expressing, Wnt-Responsive Olfactory Epithelial Progenitors Regulate Underlying Turbinate Growth to Optimize Surface Area. Dev Cell. 2018 Sep 10;46(5):564-580.e5. doi: 10.1016/j.devcel.2018.07.010.
- Huh SH*, Warchol ME, Ornitz DM*. Cochlear progenitor number is controlled through mesenchymal FGF receptor signaling, eLife. 2015 Apr 27;4. doi: 10.7554/eLife.05921. *Correspondence.
- Kim JY, Lee RH, Kim TM, Kim DW, Jeon YJ, Huh SH, OH SY, Kyba M, Kataoka H, Choi K, Ornitz DM, Chae JI, Park C. OVOL2 is a critical regulator of ER71 in generating FLK+ cells, hematopoietic and endothelial cells from embryonic stem cells, Blood. 2014 Nov 6;124(19):2948-52.
- Chen Z, Huang J, Liu Y, Dattilo LK, Huh SH, Ornitz D, Beebe DC. FGF signaling activates a Sox9-Sox10 pathway for the formation and branching morphogenesis of mouse ocular glands, Development. 2014 Jul;141(13):2691-701.
- Huh SH*, Närhi K*, Lindfors PH, Häärä O, Yang L, Ornitz DM**, Mikkola ML**. FGF20 governs formation of primary and secondary dermal condensations in developing hair follicles, Genes&Development 2013 Feb; 27: 450-458 *Equal contribution, **Correspondence. Evaluated by Faculty of 1000.
- Lin C, Yin Y, Bell SM, Veith GM, Chen H, Huh SH, Ornitz DM, Ma L. Delineating a Conserved Genetic Cassette Promoting Outgrowth of Body Appendages. PLoS Genet. 9(1): e1003231.
- Häärä O, Harjunmaa E, Lindfors PH, Huh SH, Fliniaux I, Åberg T, Jernvall J, Ornitz DM, Mikkola ML, Thesleff I. Ectodysplasin regulates activator-inhibitor balance in murine tooth development through Fgf20 signaling, Development 2012 Sep;139(17):3189-99.
- Barak H*, Huh SH*, Chen S, Jeanpierre S, Martinovic J, Parisot M, Bole-Feysot C, Nitschké P, Salomon R, Antignac C, Ornitz DM**, Kopan R**. FGF9 and FGF20 maintain the stemness of nephron progenitors in mice and man, Dev. Cell. 2012 Jun 22(6):1191-1207 *Equal contribution, **Correspondence. Previewed in ‘Dev.Cell.’ Featured in Cover Page. Evaluated by Faculty of 1000.
- Huh SH, Jones J, Warchol ME, Ornitz DM. Differentiation of the lateral compartment of the cochlea requires a temporally restricted FGF20 signal, PLoS Biology 10(1): e1001231. Highlighted in ‘Nature’. Evaluated by Faculty of 1000.
- Huh SH and Ornitz DM. b-catenin deficiency causes DiGeorge syndrome-like phenotypes through regulation of Tbx1, Development 2010 Apr;137(7):1137-47.
- Yin Y, White AC, Huh SH, Hilton MJ, Kanazawa H, Long F, Ornitz DM. An FGF-WNT gene regulatory network controls lung mesenchyme development. Dev. Biol. 2008 Jul 15;319(2):426-36.
Complete List of Publications
Brennan Roche, Grad Student EMAIL
Pooja Roy, Grad Student EMAIL
DRC II 6044