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First published online 20 April 2005
doi: 10.1242/dev.01834
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1 Institute of Biotechnology, University of Helsinki, 00014 Helsinki,
Finland
2 Departments of Medicine, Laboratory Medicine and Pathobiology and Medical
Biophysics, Division of Cell and Molecular Biology, Toronto General Research
Institute, University Health Network, University of Toronto, Toronto, Ontario
M5G-2M1, Canada
3 Creighton University, Department of Biomedical Sciences, Omaha, NE 68178,
USA
* Author for correspondence (e-mail: ulla.pirvola{at}helsinki.fi)
Accepted 23 March 2005
Precursors of cochlear and vestibular hair cells of the inner ear exit the cell cycle at midgestation. Hair cells are mitotically quiescent during late-embryonic differentiation stages and postnatally. We show here that the retinoblastoma gene Rb and the encoded protein pRb are expressed in differentiating and mature hair cells. In addition to Rb, the cyclin dependent kinase inhibitor (CKI) p21 is expressed in developing hair cells, suggesting that p21 is an upstream effector of pRb activity. p21 apparently cooperates with other CKIs, as p21-null mice exhibited an unaltered inner ear phenotype. By contrast, Rb inactivation led to aberrant hair cell proliferation, as analysed at birth in a loss-of-function/transgenic mouse model. Supernumerary hair cells expressed various cell type-specific differentiation markers, including components of stereocilia. The extent of alterations in stereociliary bundle morphology ranged from near-normal to severe disorganization. Apoptosis contributed to the mutant phenotype, but did not compensate for the production of supernumerary hair cells, resulting in hyperplastic sensory epithelia. The Rb-null-mediated proliferation led to a distinct pathological phenotype, including multinucleated and enlarged hair cells, and infiltration of hair cells into the mesenchyme. Our findings demonstrate that the pRb pathway is required for hair cell quiescence and that manipulation of the cell cycle machinery disrupts the coordinated development within the inner ear sensory epithelia.
Key words: Inner ear, Cochlea, Vestibular organ, Hair cell, Proliferation, Differentiation, Apoptosis, Cell cycle, Mitosis, Polyploidy, Rb (Rb1), p21 (Cdkn1a), Mouse
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