Lack of Rbl1/p107 Effects on Cell Proliferation and Maturation in the Inner Ear

DOI: 10.4236/jbbs.2013.37056   PDF   HTML     3,644 Downloads   5,197 Views   Citations


Loss of postnatal mammalian auditory hair cells (HCs) is irreversible. Earlier studies have highlighted the importance of the Retinoblastoma family of proteins (pRBs) (i.e., Rb1, Rbl1/p107, and Rbl2/p130) in the auditory cells’ proliferation and emphasized our lack of information on their specific roles in the auditory system. We have previously demonstrated that lack of Rbl2/p130 moderately affects HCs’ and supporting cells’ (SCs) proliferation. Here, we present evidence supporting multiple roles for Rbl1/p107 inthe developing and mature mouse organ of Corti (OC). Like other pRBs, Rbl1/p107 is expressed in the OC, particularly in the Hensen’s and Deiters’ cells. Moreover, Rbl1/p107 impacts maturation and postmitotic quiescence of HCs and SCs, as evidenced by enhanced numbers of these cells and the presence of dividing cells in the postnatal Rbl1/p107-/-OC. These findings were further supported by microarray and bioinformatics analyses, suggesting downregulation of several bHLH molecules, as well as activation of the Notch/Hes/Hey signaling pathway in homozygous Rbl1/p107 mutant mice. Physiological assessments and detection of ectopic HC marker expression in postnatal spiral ganglion neurons (SGNs) provided evidence for incomplete cell maturation and differentiation in Rbl1/p107﹣/﹣OC. Collectively, the present study highlights an important role for Rbl1/p107 inOC cell differentiation and maturation, which is distinct from other pRBs.

Share and Cite:

S. Rocha-Sanchez, L. Scheetz, S. Siddiqi, M. Weston, L. Smith, K. Dempsey, H. Ali, J. McGee and E. Walsh, "Lack of Rbl1/p107 Effects on Cell Proliferation and Maturation in the Inner Ear," Journal of Behavioral and Brain Science, Vol. 3 No. 7, 2013, pp. 534-555. doi: 10.4236/jbbs.2013.37056.

Conflicts of Interest

The authors declare no conflicts of interest.


[1] R. J. Ruben, “Development of the Inner Ear of the Mouse: A Radioautographic Study of Terminal Mitoses,” Acta Otolaryngologica, Vol. 220, No. 1, 1967, pp. 1-44.
[2] J. Mantela, Z. Jiang, J. Ylikoski, B. Fritzsch, E. Zacksenhaus and U. Pirvola, “The Retinoblastoma Gene Pathway Regulates the Postmitotic State of Hair Cells of the Mouse Inner Ear,” Development, Vol 132, No. 10, 2005, pp. 2377-2388.
[3] T. Weber, M. K. Corbett, L. M. Chow, M. B. Valentine, S. J. Baker and J. Zuo, “Rapid Cell-Cycle Reentry and Cell Death after Acute Inactivation of the Retinoblastoma Gene Product in Postnatal Cochlear Hair Cells,” Proceedings of the National Academy of Sciences USA, Vol. 105, No. 2, 2008, pp. 781-785.
[4] C. Sage, M. Huang, K. Karimi, G. Gutierrez, M. A. Vollrath, D. S. Zhang, J. Garcia-Anoveros, P. W. Hinds, J. T. Corwin, D. P. Corey and Z. Y. Chen, “Proliferation of Functional Hair Cells in Vivo in the Absence of the Retinoblastoma Protein,” Science, Vol. 307, No. 5712, 2005, pp. 1114-1118.
[5] C. Sage, M. Huang, M. A. Vollrath, M. C. Brown, P. W. Hinds, D. P. Corey, D. E. Vetter and Z. Y Chen, “Essential Role of Retinoblastoma Protein in Mammalian Hair Cell Development and Hearing,” Proceedings of the National Academy of Sciences USA, Vol 103, No. 19, 2006, pp. 7345-7350.
[6] S. M. Rocha-Sanchez and K. W. Beisel, “Pocket Proteins and Cell Cycle Regulation in Inner Ear Development,” International Journal of Developmental Biology, Vol. 51, No. 6-7, 2007, pp. 585-595.
[7] M. Huang, C. Sage, Y. Tang, S. G. Lee, M. Petrillo, P. W. Hinds and Z. Y. Chen, “Overlapping and Distinct pRb Pathways in the Mammalian Auditory and Vestibular Organs,” Cell Cycle, Vol. 10, No. 2, 2011, pp. 337-351.
[8] S. M. Rocha-Sanchez, L. R. Scheetz, M. Contreras, M. D. Weston, M. Korte, J. McGee and E. J. Walsh, “Mature Mice Lacking Rbl2/p130 Gene Have Supernumerary Inner Ear Hair Cells and Supporting Cells,” Journal of Neuroscience, Vol. 31, No. 24, 2011, pp. 8883-8893.
[9] C. Giacinti and A. Giordano, “RB and Cell Cycle Progression,” Oncogene, Vol. 25, No. 38, 2006, pp. 5220-5227.
[10] M.-H. Lee, B. O. Williams, G. Mulligan, S. Mukai, R. T. Bronson, N. Dyson, E. Harlow and T. Jacks, “Targeted Disruption of p107: Functional Overlap between p107 and Rb,” Genes & Development, Vol. 10, No. 13, 1996, pp. 1621-1632.
[11] C. Stadelmann and H. Lassmann, “Detection of Apoptosis in Tissue Sections,” Cell and Tissue Research, Vol. 301, No. 1, 2000, pp. 19-31.
[12] R. A. Irizarry, L. Gautier, B. M. Bolstad and C. Miller Affy, “Methods for Affymetrix Oligonucleotide Arrays,” 2004.
[13] G. W. Wright and R. M. Simon, “A Random Variance Model for Detection of Differential Gene Expression in Small Microarray Experiments,” Bioinformatics, Vol. 19, No. 18, 2003, pp. 2448-2455.
[14] Y. Benjamini and Y. Hochberg, “Controlling the False Discovery Rate: A Practical and Powerful Approach to Multiple Testing,” Journal of the Royal Statistical Society: Series B (Statistical Methodology), Vol. 57, No. 1, 1995, pp. 289-300.
[15] I. Ulitsky, A. Maron-Katz, S. Shavit, D. Sagir, C. Linhart, R. Elkon, A. Tanay, R. Sharan, Y. Shiloh and R. Shamir, “Expander: From Expression Microarrays to Networks and Functions,” Nature Protocols, Vol. 5, No. 2, 2010, pp. 303-322.
[16] H. Mi, A. Muruganujan and P. D. Thomas, “PANTHER in 2013: Modeling the Evolution of Gene Function, and Other Gene Attributes, in the Context of Phylogenetic Trees,” Nucleic Acids Research, Vol. 41, 2012, pp. D377-D386.
[17] C. F. Schaefer, K. Anthony, S. Krupa, J. Buchoff, M. Day, T. Hannay and K. H. Buetow, “PID: the Pathway Interaction Database,” Nucleic Acids Research, Vol. 37, 2009, pp. D674-D679.
[18] J. R. Managbanag, T. M. Witten, D. Bonchev, L. A. Fox, M. Tsuchiya, B. K. Kennedy and M. Kaeberlein, “Shortest-Path Network Analysis Is a Useful Approach toward Identifying Genetic Determinants of Longevity,” PLoS One, Vol. 3, No. 11, 2008, Article ID: e3802.
[19] D. Phippard, L. Lu, D. Lee, J. C. Saunders and E. B. Crenshaw, “Targeted Mutagenesis of the POU-Domain Gene Brn4/Pou3f4 Causes Developmental Defects in the Inner Ear,” Neuroscience, Vol. 19, No. 14, 1999, pp. 5980-5989.
[20] F. J. Kubben, A. Peeters-Haesevoets, L. G. Engels, C. G. Baeten, B. Schutte, J. W. Arends, R. W. Stockbrugger and G. H. Blijham, “Proliferating Cell Nuclear Antigen (PCNA): A New Marker to Study Human Colonic Cell Proliferation,” Gut, Vol. 35, No. 4, 1994, pp. 530-535.
[21] X. Mayol and X. Grana, “pRB, p107 and p130 as Transcriptional Regulators: Role in Cell Growth and Differentiation,” Progress in Cell Cycle Research, Vol. 3, 1997, pp. 157-169.
[22] X. Grana, J. Garriga and X. Mayol, “Role of the Retinoblastoma Protein Family, pRB, p107 and p130 in the Negative Control of Cell Growth,” Oncogene, Vol. 17, No. 25, 1998, pp. 3365-3383.
[23] M. M. Lipinski and T. Jacks, “The Retinoblastoma Gene Family in Differentiation and Development,” Oncogene, Vol. 18, No. 55, 1999, pp. 7873-7882.
[24] J. Murata, K. Ikeda and H. Okano, “Notch Signaling and the Developing Inner Ear,” Advances in Experimental Medicine and Biology, Vol. 727, 2012, pp. 161-173.
[25] B. H. Hartman, T. A. Reh and O. Bermingham-McDonogh, “Notch Signaling Specifies Prosensory Domains via Lateral Induction in the Developing Mammalian Inner Ear,” Proceedings of the National Academy of Sciences USA, Vol. 107, No. 33, 2010, pp. 15792-15797.
[26] J. Murata, T. Ohtsuka, A. Tokunaga, S. Nishiike, H. Inohara, H. Okano and R. Kageyama, “Notch-Hes1 Pathway Contributes to the Cochlear Prosensory Formation Potentially through the Transcriptional Down-Regulation of p27Kip1,” Journal of Neuroscience Research, Vol. 87, No. 16, 2009, pp. 3521-3534.
[27] K. Mizutari, M. Fujioka, M. Hosoya, N. Bramhall, H. J. Okano, H. Okano and A. S. Edge, “Notch Inhibition Induces Cochlear Hair Cell Regeneration and Recovery of Hearing after Acoustic Trauma,” Neuron, Vol. 77, No. 1, 2013, pp. 58-69.
[28] N. A. Bermingham, B. A. Hassan, S. D. Price, M. A. Vollrath, N. Ben-Arie, R. A. Eatock, H. J. Bellen, A. Lysakowski and H. Y. Zoghbi, “Math1: An Essential Gene for the Generation of Inner Ear Hair Cells,” Science, Vol. 284, No. 5421, 1999, pp. 1837-1841.
[29] J. M. Jones, M. Montcouquiol, A. Dabdoub, C. Woods and M. W. Kelley, “Inhibitors of Differentiation and DNA Binding (Ids) Regulate Math1 and Hair Cell Formation during the Development of the Organ of Corti,” Journal of Neuroscience, Vol. 26, No. 2, 2006, pp. 550-558.
[30] B. Fritzsch, D. F. Eberl and K. W. Beisel, “The Role of bHLH Genes in Ear Development and Evolution: Revisiting a 10-Year-Old Hypothesis,” Cellular and Molecular Life Sciences, Vol. 67, No. 18, 2010, pp. 3089-3099.
[31] M. Ozeki, E. P. Schlentz and J. Lin, “Characterization of Inhibitor of Differentiation (Id3) Gene Expression in the Developing Cochlear Tissue of Rats,” Acta Otolaryngologica, Vol. 125, No. 3, 2005, pp. 244-249.
[32] A. Lasorella, A. Iavarone and M. A. Israel, “Id2 Specifically Alters Regulation of the Cell Cycle by Tumor Suppressor Proteins,” Molecular and Cellular Biology, Vol. 16, No. 6, 1996, pp. 2570-2578.
[33] Z. Zebedee and E. Hara, “Id Proteins in Cell Cycle Control and Cellular Senescence,” Oncogene, Vol. 20, No. 58, 2001, pp. 8317-8325.
[34] Y. Yokota and S. Mori, “Role of Id Family Proteins in Growth Control,” Journal of Cellular Physiology, Vol. 190, No. 1, 2002, pp. 21-28.
[35] Q. L. Ying, J. Nichols, I. Chambers and A. Smith, “BMP Induction of Id Proteins Suppresses Differentiation and Sustains Embryonic Stem Cell Self-Renewal in Collaboration with STAT3,” Cell, Vol. 115, No. 3, 2003, pp. 281-292.
[36] D. L. Burkhart, S. E. Wirt, A. F. Zmoos, M. S. Kareta and J. Sage, “Tandem E2F Binding Sites in the Promoter of the p107 Cell Cycle Regulator Control p107 Expression and Its Cellular Functions,” PLoS Genet, Vol. 6, 2010, Article ID: e1001003.
[37] M. A. Parker, D. A. Corliss, B. Gray, J. K. Anderson, R. P. Bobbin, E. Y. Snyder and D. A. Cotanche, “Neural Stem Cells Injected into the Sound-Damaged Cochlea Migrate throughout the Cochlea and Express Markers of Hair Cells, Supporting Cells, and Spiral Ganglion Cells,” Hearing Research, Vol. 232, No. 1-2, 2007, pp. 29-43.
[38] D. Cobrinik, M. H. Lee, G. Hannon, G. Mulligan, R. T. Bronson, N. Dyson, E. Harlow, D. Beach, R. A. Weinberg and T. Jacks, “Shared Role of the pRB-Related p130 and p107 Proteins in Limb Development,” Genes & Development, Vol. 10, No. 13, 1996, pp. 1633-1644.
[39] J. H. Dannenberg, L. Schuijff, M. Dekker, M. van der Valk and H. te Riele, “Tissue-Specific Tumor Suppressor Activity of Retinoblastoma Gene Homologs p107 and p130,” Genes & Development, Vol, 18, No. 23, 2004, pp. 2952-2962.
[40] L. Song, J. McGee and E. J. Walsh, “Frequency-and Level-Dependent Changes in Auditory Brainstem Responses (ABRS) in Developing Mice,” Journal of the Acoustical Society of America, Vol. 119, No. 4, 2006, pp. 2242-2257.
[41] J. L. Vanderluit, K. L. Ferguson, V. Nikoletopoulou, M M. Parker, V. Ruzhynsky, T. Alexson, S. M. McNamara, D. S. Park, M. Rudnicki and R. S. Slack, “p107 Regulates Neural Precursor Cells in the Mammalian Brain,” Journal of Cell Biology, Vol. 166, No. 6, 2004, pp. 853-863.
[42] J. L. Vanderluit, C. A. Wylie, K. A. McClellan, N. Ghanem, A. Fortin, S. Callaghan, J. G. MacLaurin, D. S. Park and R. S. Slack, “The Retinoblastoma Family Member p107 Regulates the Rate of Progenitor Commitment to a Neuronal Fate,” Journal of Cell Biology, Vol. 178, No. 1, 2007, pp. 129-139.
[43] A. K. Groves, “The Challenge of Hair Cell Regeneration,” Experimental Biology and Medicine, Vol. 235, No. 4, 2010, pp. 434-446.
[44] B. Fritzsch, K. W. Beisel and L. A. Hansen, “The Molecular Basis of Neurosensory Cell Formation in Ear Development: A Blueprint for Hair Cell and Sensory Neuron Regeneration?” Bioessays, Vol. 28, No. 12, 2006, pp. 1181-1193.
[45] P. Chen and N. Segil, “p27(Kip1) Links Cell Proliferation to Morphogenesis in the Developing Organ of Corti,” Development, Vol. 126, No. 8, 1999, pp. 1581-1590.
[46] T. Tateya, I. Imayoshi, I. Tateya, J. Ito and R. Kageyama, “Cooperative Functions of Hes/Hey Genes in Auditory Hair Cell and Supporting Cell Development,” Developmental Biology, Vol. 352, No. 2, 2011, pp. 329-340.
[47] D. Lyden, A. Z. Young, D. Zagzag, W. Yan, W. Gerald, R. O’Reilly, B. L. Bader, R. O. Hynes, Y. Zhuang, K. Manova and R. Benezra, “Id1 and Id3 Are Required for Neurogenesis, Angiogenesis and Vascularization of Tumour Xenografts,” Nature, Vol. 401, No. 6754, 1999, pp. 670-677.
[48] A. Iavarone, P. Garg, A. Lasorella, J. Hsu and M. A. Israel, “The Helix-Loop-Helix Protein Id-2 Enhances Cell Proliferation and Binds to the Retinoblastoma Protein,” Genes & Development, Vol. 8, No. 11, 1994, pp. 1270-1284.
[49] J. L. Rodriguez, J. Sandoval, G. Serviddio, J. Sastre, M. Morante, M. G. Perrelli, M. L. Martinez-Chantar, J. Vina, J. R. Vina, J. M. Mato, M. A. Avila, L. Franco, G. Lopez-Rodas and L. Torres, “Id2 Leaves the Chromatin of the E2F4-p130-Controlled c-myc Promoter during Hepatocyte Priming for Liver Regeneration,” Biochemical Journal, Vol. 398, No. 3, 2006, pp. 431-437.
[50] S. D. Morgenbesser, B. O. Williams, T. Jacks and R. A. Depinho, “p53-Dependent Apoptosis Produced by Rb-Deficiency in the Developing Mouse Lens,” Nature, Vol. 371, No. 6492, 1994, pp. 72-74.
[51] H. Laine, M. Sulg, A. Kirjavainen and U. Pirvola, “Cell Cycle Regulation in the Inner Ear Sensory Epithelia: Role of Cyclin D1 and Cyclin-Dependent Kinase Inhibitors,” Developmental Biology, Vol. 337, No.1, 2010, pp. 134-146.
[52] B. Levkau, H. Koyama, E. W. Raines, B. E. Clurman, B. Herren, K. Orth, J. M. Roberts and R. Ross, “Cleavage of p21Cip1/Waf1 and p27Kip1 Mediates Apoptosis in Endothelial Cells through Activation of Cdk2: Role of a Caspase Cascade,” Molecular Cell, Vol. 1, No. 4, 1998, pp. 553-563.

comments powered by Disqus

Copyright © 2020 by authors and Scientific Research Publishing Inc.

Creative Commons License

This work and the related PDF file are licensed under a Creative Commons Attribution 4.0 International License.