Education:
BA 1975 Hampshire College, Amherst, Massachusettes
PhD 1989 Columbia University, New York City, New York
Postdoctoral Research Fellowship:
1987-1989 Ernst Boehringer Institute, Vienna, Austria
1989-1996 Rockefeller University, New York
Started at USC: 1996
Research Topics: Cell Cycle, Growth & Proliferation, Developmental Biology, Aging, Gene Regulation/Transcription, Neurogenetics, Cellular Neurobiology
Research Description
Cell cycle regulation during the development and regeneration of the inner ear.
Most hearing and balance problems are due to the death of sensory hair cells located in the organ of Corti and vestibular system of the mammalian inner ear. In lower vertebrates these cells are able to regenerate, but in mammals they are not. The biochemical pathways that control the cell cycle and cell differentiation in the sensory epithelium of the inner ear are the key to understanding this difference and as such are likely to provide targets for possible therapeutic attempts at manipulating regeneration.
The central question is how cell proliferation in the developing inner ear is coordinated with the process of differentiation and morphogenesis. Our laboratory has discovered that one element required for this coordination in the developing inner ear is p27Kip1, a cyclin-dependent kinase inhibitor that plays an important role in regulating cell number in a variety of developing tissues (1). During the development of the sensory epithelia of the inner ear, the expression of p27Kip1 is up-regulated as progenitor cells exit the cell cycle. In p27Kip1 mutant animals, mitotic activity in the developing organ of Corti is prolonged relative to wild type, leading to the production of supernumerary sensory hair cells and supporting cells. In wild type animals, p27Kip1 is down-regulated in differentiating hair cells shortly after their withdrawal from the cell cycle on embryonic day 14, but its expression persists in the supporting cells into adulthood. This observation suggests that regulation of p27Kip1 levels may not only be important during embryonic development, but also may be crucial for the maintenance of the differentiated state and thus be an obstacle to regeneration in mammals.
Although these results indicate that p27Kip1 plays an important role in the developmental timing of cell cycle withdrawal in the primordial organ of Corti, mutation of the p27Kip1 gene does not result in runaway proliferation, suggesting the presence of additional factors mediating cell cycle withdrawal. We are actively engaged in identifying those other factors.
This work is supported by the Oberkotter Foundation and the National Institute of Health.
Selected Publications
Jayasena CS, Ohyama T, Segil N, Groves AK. - Notch signaling augments the canonical Wnt pathway to specify the size of the otic placode. - Development [ 2008 ] May 21; . PubMed
Raft S, Koundakjian EJ, Quinones H, Jayasena CS, Goodrich LV, Johnson JE, Segil N, Groves AK. - Cross-regulation of Ngn1 and Math1 coordinates the production of neurons and sensory hair cells during inner ear development. - Development [ 2007 ] Dec;134(24):4405-15 . PubMed
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 . PubMed
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 . PubMed
Lee YS, Liu F, Segil N. - A morphogenetic wave of p27Kip1 transcription directs cell cycle exit during organ of Corti development. - Development [ 2006 ] Aug;133(15):2817-26 . PubMed
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 . PubMed
Wang J, Hamblet NS, Mark S, Dickinson ME, Brinkman BC, Segil N, Fraser SE, Chen P, Wallingford JB, Wynshaw-Boris A. - Dishevelled genes mediate a conserved mammalian PCP pathway to regulate convergent extension during neurulation. - Development [ 2006 ] May;133(9):1767-78 . PubMed
Radde-Gallwitz K, Pan L, Gan L, Lin X, Segil N, Chen P. - Expression of Islet1 marks the sensory and neuronal lineages in the mammalian inner ear. - J Comp Neurol [ 2004 ] Sep 27;477(4):412-21 . PubMed
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 . PubMed
