Fuxin Shi, Ph.D.
Instructor of Otology and Laryngology, Harvard Medical School
The objective of our research is to investigate molecular pathways in hair cell development, and to exploit these pathways in order to regenerate sensory hair cells and restore hearing. We aim to also explore novel methods for the prevention of hair cell loss during ototoxic insult and acoustic trauma.
Wnt/beta-catenin signaling is a well-known pathway essential for stem cell maintenance and differentiation. In the ear, we found that Wnt signaling controls the expression of Atoh1, which is a key gene in hair cell development. In a recent study, we identified one downstream target of Wnt signaling to be a marker of inner ear stem cells. The Wnt pathway controls the fate of those stem cells during neonatal development. Specifically, in the developing embryo, Wnt signaling is active in inner ear stem cells at the time that hair cell differentiation is taking place, but disappears in the mature inner ear despite the persistence of inner ear stem cells. These findings suggest that the lack of regenerative ability in the inner ear can be attributed, at least in part, to the loss of Wnt signaling. Based on our studies, we will develop novel strategies to re-activate Wnt signaling in inner ear stem cells in order to regenerate hair cells.
Schematic diagram illustrates regulation of Atoh1 by beta-catenin. The positive sign and arrow represent the increased transcription of Atoh1 upon binding of beta-catenin-Tcf/Lef to the Atoh1 3'-enhancer. The resulting Atoh1 product acts to upregulate its own expression by binding to the same enhancer. Stimulation by beta-catenin accounts for the upregulation of Atoh1 after Notch inhibition.
1. Shi, F., Kempfle, J., Edge, A.S. Lgr5 marks Wnt-responsive hair cell progenitors in the cochlea. Submitted.
2. Shi, F., Chen, Y., Wang, X., Edge, A.S. Beta-catenin up-regulates Atoh1 expression in neural progenitor cells by interaction with an Atoh1 3' enhancer. Journal of Biochemical Chemistry 2010; 285:392-400.
3. Shi, F., Corrales, C.E., Liberman, M.C., Edge, A.S. BMP4 induction of sensory neurons from human embryonic stem cells and reinnervation of sensory epithelium. European Journal of Neuroscience 2007; 26:3016-3023.
4. Shi, F., Gounko, N.V., Wang, X., Ronken, E., Hoekstra, D. In situ entry of oligonucleotides into brain cells can occur through a nucleic acid channel. Oligonucleotides 2007; 17:123-133.
5. Shi, F., Visser, W.H., de Jong, N.M., Liem, R.S., Ronken, E., Hoekstra, D. Antisense phosphothioate oligonucleotides interact via the RNA matrix to reach the targe 20t mRNA. Downregulation of the 5-HT1A receptor. Experimental Cell Research 2003; 291:313-325.
6. Shi, F., Wasungu, L., Nomden, A., Stuart, M.C., Polushkin, E., Engberts, J.B., Hoekstra, D. Interference of poly(ethylene glycol)-lipid analogues with cationic-lipid-mediated delivery of oligonucleotides; role of lipid exchangeability and non-lamellar transitions. Biochemical Journal 2002; 366:333-341.
7. Shi, F., Nomden, A., Oberle, V., Engberts, J.B., Hoekstra, D. Efficient cationic lipid-mediated delivery of antisense oligonucleotides into eukaryotic cells: down-regulation of the corticotropin-releasing factor receptor. Nucleic Acids Research 2001; 29:2079-2087.
8. Wang, S., Shi, F., Wosten, H.A., Hektor, H., Poolman, B., Robillard, G.T. Unidirectional permeability of hydrophobin SC3 membrane formed at an oil/water interface. Biophysical Journal 2005; 88:3434-3443.
9. Swinny, J.D., Kalicharan, D., Brouwer, N., Biber, K.,Shi, F., Gramsbergen, A., van der Want, J.J. The postnatal development expression pattern of urocortin in the rat oligocerebellar system. Journal of Comparative Neurology 2004; 472:40-51.
10. Swinny, J.D., Kalicharan, D., Blaauw, E.H., Ijkema-Paassen, J., Shi, F., Gramsbergen, A., van der Want, J.J. Corticotropin releasing factor types 1 and 2 are differentially expressed in pre- and postsynaptic elements in the postnatal developing rat cerebellum. European Journal of Neuroscience 2003; 18:549-562.