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Section on Sensory Cell Regeneration and Development
Doris K. Wu, Ph.D., Chief
Morphogenesis of the mouse inner ear from embryonic day 10.75 to postnatal day 1. Mouse specimens from various ages were fixed, cleared, and the lumen of the inner ear was filled with a latex paint solution (Cantos et al. 2000; for a detailed description of this paint filling technique, see Morsli et al. 1998).
We rely on the inner ear, an intricate sensory organ, to hear and to maintain balance. Formation of this organ is a complex process that occurs in a precise temporal sequence16. This temporal sequence is largely initiated by cues from tissues surrounding the ear primordium, followed by a cascade of molecular events within the ear tissue. Any missteps in this process will most likely result in some degree of dysfunction affecting the abilities to hear and maintain balance.
The goal of the laboratory is to identify the molecular mechanisms underlying the formation of this complex structure. Using mouse, chicken, and zebrafish as animal models, we focus on identifying the external cues that instruct the ear rudiment about its positional information—for example, where to form the cochlea (hearing apparatus) versus the semi-circular canals (non-sensory vestibular structures)2–6,12,14,17. Another focus of the laboratory is to determine the cascades of events induced by external cues, which specify all aspects of inner ear development including the three primary cell types (neural, sensory, and nonsensory) of the ear rudiment2 and the identity of each sensory structure and the types of sensory hair cells and polarity within2,7–11,13,15. By understanding the normal development of the inner ear at a molecular level, we may help to design better strategies to alleviate hearing and balancing disorders.
- Jiang T., Kindt K., Wu, D.K. Transcription factor Emx2 controls stereociliary bundle orientation of sensory hair cells. Nathans J, ed. eLife. 2017;6:e23661. doi:10.7554/eLife.23661.
- Raft, S., Andrade, L.R., Shao, D., Akiyama, H., Henkemeyer, M., Wu, D.K. Ephrin-B2 governs morphogenesis of endolymphatic sac and duct epithelia in the mouse inner ear. Dev Biol. 390:51–67, 2014.
- Evsen, L., Sugahara, S., Uchikawa, M., Kondoh H., Wu, D.K. Progression of neurogenesis in the inner ear requires inhibition of Sox2 transcription by neurogenin1 and neurod1. J Neurosci. 2013; vol33(9), pp 3879–90, 2013.
- Bok, J., Zenczak, C., Hwang, C.H., Wu, D. K. Auditory ganglion source of Sonic hedgehog regulates timing of cell cycle exit and differentiation of mammalian cochlear hair cells. PNAS, 2013, vol 110 no.34, pp.13869–13874.
- Bok, J., Raft, S., Kong, K., Koo, S.K., Dräger, U.C., Wu, D.K. Transient retinoic acid signaling confers anterior-posterior polarity to the inner ear. Proc Natl. Acad Sci. 108:161–166, 2011.
- Liang, J. K., Bok, J. and Wu, D. K. Distinct contributions from the hindbrain and mesenchyme to inner ear morphogenesis. Dev Bio. 337:324–34, 2010.
- Koo, S.K., Hill, J.K., Hwang C.H., Lin, Z.S., Millen, K.J., Wu, D.K. Lmx1a maintains proper neurogenic, sensory, and non-sensory domains in the mammalian inner ear. Dev Bio. 333:14–25, 2009.
- Chang, W., Lin, Z., Kulessa, H., Hebert, J., Hogan, B.L.M., and Wu, D. K. Bmp4 is essential for the formation of the vestibular apparatus that detects angular head movements. PLoS Genetics, 4:e1000050, 2008.
- Hwang, C. and Wu, D. K. Noggin heterozygous mice: an animal model for congenital conductive hearing loss in humans. Human Mol Genetics, 17:844–853, 2008.
- Bok, J., Dolson, D. K., Hill, P., Ruther, U., Epstein, D. J. and Wu, D. K. Opposing gradients of Gli repressor and activators mediate Shh signaling along the dorsoventral axis of the inner ear. Development, 134:1713–1722, 2007.
- Lin, Z., Cantos, R., Patente, M. and Wu, D. K. Gbx2 is required for the morphogenesis of the mouse inner ear: a downstream candidate of hindbrain signaling. Development, 132:2309–2318, 2005.
- Bok, J., Bronner-Fraser, M., and Wu, D. K. Role of the hindbrain in dorsoventral but not anteroposterior axial specification of the inner ear. Development,132:2115–2124, 2005.
- Chang, W., Brigande, J., Fekete, D. and Wu, D. K. The development of semicircular canals in the inner ear: role of FGFs in sensory cristae. Development, 131:4201–4211, 2004.
- Riccomagno, M., Martinu, L., Mulheisen, M., Wu, D. K., and Epstein, D. Specification of the mammalian cochlea is dependent on Sonic hedgehog. Genes & Dev, 16:2365–2378, 2002.
- Cantos, R., Cole, L., Acampora, D., Simeone, A. and Wu, D. K. Patterning of the mammalian cochlea. Proc Natl Acad Sci, 97:11707–11713, 2000.
- Morsli, H., Choo D., Ryan, A., Johnson, R. and Wu, D.K. Development of the mouse inner ear and origin of its sensory organs. J Neurosci, 18:3327–3335, 1998.
- Wu, D. K., Nunes, F. and Choo, D. Axial specification for sensory organs versus non-sensory structures of the chicken inner ear. Development, 125:11–20, 1998.