725 N. Wolfe Street
Baltimore, MD 21205
MECHANOTRANSDUCTION AND AUDITORY PERCEPTION
Hair cells in the inner ear are mechanosensors for the perception of sound and head movements. Sound signals directly activate mechanically gated ion channels in hair cells, leading to hair cell depolarization and the release of neurotransmitters onto afferent neurons. Of all our senses, the mechanical senses are the least well understood. My laboratory uses genetic strategies to identify components of the mechanotransduction machinery of hair cells. Using ENU mutagenesis, we have generated mouse lines that are afflicted with deafness. We have cloned the affected genes and studied their function for auditory perception. Using this strategy, we have identified several components of the mechanotransduction machinery of hair cells. All of the identified genes are linked to auditory impairment in humans. Current efforts are aimed at the identification of additional components of the mechanotransduction machinery of hair cells and at the mechanisms by which these proteins are regulated by mechanical force. We are also identifying genes and mechanisms important for the assembly of auditory circuits essential for the processing of sound signals in the CNS.
NEURAL STEM CELLS AND NEOCORTICAL DEVELOPMENT
A second project analyzes the mechanisms that regulate the differentiation of neural stem cells during neocortical development, and how neurons that are derived from stem cells are integrated into neocortical circuits. We have identified neuronal progenitors that generate subclasses of excitatory projection neurons in the neocortex. We have also defined some of the mechanisms by which these neurons migrate into the developing neocortex. Current projects define the genetic and epigenetic mechanisms that instruct the fate of neuronal progenitors and that lead to the generation of distinct subtypes of neocortical projection neurons. More recently, we have begun to study not only the neocortex of mice but also of ferrets, marmosets, and humans including the analysis of the function of genes linked to neurological and psychiatric disorders.
Sun, S. Babola, T., Pregernig, G., So, K., Nguyen, M., Su, M., Palermo, A., Bergles, D.E., Burns, J. and Müller, U. (2018). Hair Cell Mechanotransduction Regulates Spontaneous Activity and Spiral Ganglion Subtype Specification in the Auditory System. Cell 174, 1247-1263.
Cunningham, C.L., Wu, Z., Jafari, A., Zhao, B., Schrode, K., Harkins-Perry, S., Lauer, A., Müller, U. (2017). The murine catecholamine methyltransferase mTOMT is essential for mechanotransduction by cochlear hair cells. Elife 6, e24318.
Wu, Z., Grillet, N., Zhao, B., Cunningham, C., Harkins-Perry, S., Coste, B., Ranade, S., Zebarjadi, N., Beurg, M., Fettiplace, R., Patapoutian, A., and Müller, U. (2017). Mechanosensory hair cells express two molecularly distinct mechanotransduction channels. Nat Neurosci. 20, 24-33.
Zhao, B., Wu. Z, and Müller, U. (2016) Murine Fam65b forms ring-like structures at the base of stereocilia critical for mechanosensory hair cell function. Elife, 5, e14222.
Xiong, W., Wagner, T., Yan, L., Grillet, N., and Müller, U. (2014). Injectoporation: An efficient gene delivery method for the annotation of gene function in mechanosensory hair cells. Nature Protocols 9, 2438-2494.
Müller, U., and Gillespie, P. (2015). New treatment options for hearing loss. Nat. Rev. Drug Discovery 14, 346-365.
Gil-Sanz, C., Espinosa A., Fregoso S.P., Bluske, K.K., Cunningham, C.L., Martinez-Garay, I., Zeng, H., Franco,S.J., and Müller, U. (2014). Linege tracing using Cux2-Cre and Cux2-CreERT2 mice. Neuron 86,1091-1099.
Zhao, B., Wu, Z., Grillet, N., Yan, L., Xiong. W., Harkins-Perry, S., and Müller, U. (2014). TMIE is an essential component of the mechanotransduction machinery of cochlear hair cells. Neuron 84, 954-967.
Gil-Sanz, C., Franco, S.J., Martinez-Garay, I., Espinosa, A., Harkins-Perry, S., and Müller, U. (2013). Cajal-Retzius cells instruct neuronal migration by coincidence signaling between secreted and contact-dependent guidance cues. Neuron 79, 461-477.
Xiong, W., Grillet, N., Elledge, H., Wagner, T.F.J., Zhao, B, Johnson, K.R., Kazmierczak, P., and Müller, U. (2012). TMHS is an Integral Component of the Mechanotransduction Machienry of Cochlear Hair Cells. Cell 151, 1283-1295.
Franco S.J., and Müller, U. (2012). Shaping our minds: stem and progenitor cell diversity in the mammalian neocortex. Neuron 77, 19-34.
Franco, S.J., Gil-Sanz, C. Martinez-Garay, I., Espinosa, A., Harkins-Perry, S.R., Ramos, C., and Müller, U. (2012). Fate-Restricted Neural Progenitors in the Mammalian Cerebral Cortex. Science 337, 746-749.
Reelin signaling regulates cadherin function through Dab1/Rap1 to regulate migration and lamination in the cerebral cortex. Franco, S.J., Martinez-Garay, I., Gil-Sanz, C., Harkins-Perry, S.R., and Müller, U. (2011). Neuron 69, 482-497.
Gillespie, P., and Müller, U. (2009). Mechanotransduction by Hair Cells: Models, Molecules, and Mechanisms. Cell 139, 33-44.
Grillet, N., Xiong, W., Reynolds, A., Kazmierczak, P., Sato, T., Lillo, C., Dumont, R.A., Hintermann, E., Sczaniecka, A., Schwander, M., Williams, D., Kachar, B., Gillespie, P.G., and Müller, U. (2009) Harmonin mutations cause mechanotransduction defects in cochlear hair cells. Neuron 62, 345-387. (Cover Article)
Kazmierczak, P.$, Sakaguchi, H., Tokita, J., Wilson-Kubalek, E.M., Milligan, R.A., Müller, U.*, and Kachar, B.* (2007). Cadherin 23 and protocadherin 15 interact to form tip-link filaments in sensory hair cells. Nature 449, 87-91.
$ First author from Müller laboratory, * co-corresponding authors Siemens, J., Lillo, C., Dumont, R.A., Williams, D., Gillespie, P.G., and Müller, U. (2004) CDH23 is a component of the tip link in hair cell stereocilia. Nature 428, 950-955.
Siemens, J., Lillo, C., Dumont, R.A., Williams, D., Gillespie, P.G., and Müller, U. (2004) CDH23 is a component of the tip link in hair cell stereocilia. Nature 428, 950-955./p