Research Associate Professor, Department of Cell and Neurobiology
Division of Cell Biology and Genetics, House Ear Institute
- embryonic development of the inner ear
- sensory hair cell regeneration
- cell cycle control during development
- cellular homeostasis – DNA repair
- stem/progenitor cell biology
Research Overview1) Embryonic development of the inner ear:
Coordinating cell proliferation, growth and differentiation is crucial for the development of animal form. This project investigates the biochemical machinery responsible for this coordination. We are investigating the role and regulation of cyclin-dependent kinase inhibitors (CKIs) in the formation of the prosensory domains in the inner ear, the cells that give rise to the organ of Corti and the vestibular sensory areas. In addition, we are studying the biochemical basis for hair cell and supporting cell differentiation within the developing mosaic of the sensory epithelia, and its relation to the stability of the differentiated state. In particular, we are studying the epigenetic regulation of transcription associated with Notch-dependent signaling within this system.
2) Sensory cell regeneration – postnatal changes in progenitors/stem cells of the inner ear:
We are engaged in identifying and manipulating sensory progenitors/stem cells in postnatal mice as potential targets for therapeutic approaches through regeneration. We have developed tools, in the form of cell-type specific markers and purification techniques, as well as cell culture methods for studying the behavior of sensory cell progenitors. We are currently using these tools to characterize the lineage and regenerative potential of specific cell populations within the postnatal inner ear.
3) Homeostasis and repair in the aging nervous system: the cell cycle, DNA damage and DNA repair:
The goal of this project is to understand the basis for the lifelong homeostatic maintenance of permanently postmitotic cells in the nervous system, including the inner ear. Sensory hair cells, like most neurons, stop dividing either in the embryo or shortly after birth. If lost due to environmental stress (loud noise, chemotherapy agents, antibiotics, aging) these cells do not regenerate. This means that lifelong cell renewal/repair must occur on an ongoing basis in the absence of cell replacement and in the presence of strong control over cell division. These factors are associated with a heightened sensitivity to physiological/environmental stress. Our focus is on how the cell cycle machinery in hair cells contributes to their sensitivity to stress, and how these pathways interact with other homeostatic pathways, such as those involved in DNA damage and repair. Currently, we are studying mouse models of the human DNA repair disorder, Cockayne Syndrome, which is associated with aspects of premature aging, and, as our current research indicates, sensory-neural hearing loss.
- Web Sites:
- Segil Lab Home Page
Training in Hearing & Communication Neuroscience
- Mailing Address:
- House Ear Institute
Division of Cell Biology and Genetics
2100 West Third Street
Los Angeles, CA 90057
- Office Location:
- House Ear Institute
- Office Phone:
- (213) 273-8082
- Lab Location:
- House Ear Institute
- (213) 273-8088
- B.A., Hampshire College, Amherst, MA, 1975.
- Ph.D., Columbia University, New York, NY, 1989.
Doetzlhofer, A., Basch, M. Gessler, M., Groves, A. K., and Segil, N. (2009). Hey2 regulation by FGF provides a Notch-independent mechanism for maintaining pillar cell fate in the organ of Corti. Developmental Cell 16: 58-69. -PubMed
Raft S, Koundakjian EJ, Quinones H, Jayasena CS, Goodrich LV, Johnson JE, Segil N, Groves AK. (2007) Cross-regulation of Ngn1 and Math1 coordinates the production of neurons and sensory hair cells during inner ear development. Development. 134(24):4405-15. -PubMed
White, P.M., Doetzlhofer, A., Lee, Y.-S., Groves, A.K., and Segil, N. (2006) Mammalian cochlear supporting cells can divide and trans-differentiate into hair cells. Nature 441:984-987. -PubMed
Lee, Y.-S. Liu, F., and Segil, N (2006). Transcriptional Regulation of p27Kip1 Directs a Morphogenetic Wave of Cell Cycle Exit in the Developing Organ of Corti. Development 133:2817-26. -PubMed
Laine H, Doetzlhofer A, Mantela J, Ylikoski J, Laiho M, Roussel MF, Segil N, Pirvola U. (2007) 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. 27(6):1434-44. -PubMed
Chen, P., Zindy, F., Abdala, C., Liu, F., Li, X., Roussel, M.F., and Segil, N. (2003). Progressive hearing loss in mice lacking the cyclin-dependent kinase inhibitor Ink4d. Nature Cell Biology 5:422-426 -PubMed
Chen P, Segil N. (1999) p27Kip1 links cell proliferation to morphogenesis in the developing organ of Corti. Development 126:1581-1590. -PubMed
Segil N, Guermah M, Hoffmann A, Roeder RG, Heintz N. (1996) Mitotic regulation of TFIID: Inhibition of activator-dependent transcription and changes in sub-cellular localization. Genes and Development 10:2389-2400. -PubMed
Segil N, Roberts SB, Heintz N. (1991) Mitotic phosphorylation of the Oct-1 POU-homeodomain and the regulation of Oct-1 DNA binding activity. Science 254:1814-1816. -PubMed