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Cell specification and differentiation in the mammalian auditory system
Auditory hair cells, located in the inner ear cochlea are critical for our ability to detect sound. In mammals, neural innervated hair cells come in two flavors: inner hair cells, which are our primary mechanoreceptor and relay sound information to the brain and the signal amplifying outer hair cells. Inner and outer hair cells are structurally and functionally supported by different types of glial like supporting cells with which they share a close lineage relationship. Despite their importance for our ability to hear, little is known about how the different hair cell and supporting cell lineages are specified and what molecular cues trigger their differentiation. A main goal of my laboratory is to identify and characterize the molecular mechanisms underlying hair cell and supporting cell specification and differentiation in the mammalian auditory system. An associated interest is to identify the molecular roadblocks preventing mammalian hair cell regeneration. In mammals, hair cell generation is limited to embryonic development. Lost hair cells are not replaced leading to deafness and balance disorders. However, in non-mammalian vertebrates, supporting cells undergo a process of de-differentiation after hair cell loss, and are able to replace lost hair cells by either cell division or direct trans-differentiation. We recently showed that purified mammalian supporting cells retain some hair cell progenitor-like qualities and are able to trans-differentiate into hair cell in vitro. These results suggest that the lack of mammalian hair cell regeneration is likely due to an absence or blockage of regenerative signals. Currently projects in the laboratory address: 1) Function of Hes and Hey transcription factors in supporting cell differentiation and maintenance; 2) Extracellular signals, that control supporting cell maintenance and potentially limit hair cell regeneration; 3) Identification of nuclear factors that control specification of hair cell and supporting cell subtypes. Our investigations make use of mouse genetic approaches, including inner ear-specific conditional gene targeting and in vitro manipulations of gene function in cochlea tissue and primary cell culture systems.
Doetzlhofer A, Basch ML, Ohyama T, Gessler M, Groves AK, Segil N. Hey2 regulation by FGF provides a Notch-independent mechanism for maintaining pillar cell fate in the organ of Corti. Dev Cell. 2009 Jan;16(1):58-69.
Laine H, Doetzlhofer A, Mantela J, Ylikoski J, Laiho M, Roussel MF, Segil N, Pirvola U. p19(Ink4d) and p21(Cip1) collaborate to maintain the postmitotic state of auditory hair cells, their codeletion leading to DNA damage and p53-mediated apoptosis. J Neurosci. 2007 Feb 7;27(6):1434-44.
White PM*, Doetzlhofer A*, Lee YS, Groves AK, Segil N. Mammalian cochlear supporting cells can divide and trans-differentiate into hair cells. Nature. 2006 Jun 22; 441 (7096): 984-7. *These authors contributed equally to this work.
Doetzlhofer A, White P, Lee YS, Groves A, Segil N. Prospective identification and purification of hair cell and supporting cell progenitors from the embryonic cochlea. Brain Res. 2006 May 26; 1091(1):282-8.
Doetzlhofer A, White PM, Johnson JE, Segil N, Groves AK. In vitro growth and differentiation of mammalian sensory hair cell progenitors: a requirement for EGF and periotic mesenchyme. Dev Biol. 2004 Aug 15;272(2):432-47.