Abstract
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.
Highlights
Differentiation of inner ear sensory hair cells (HCs) and their associated non-sensory supporting cells (SCs) follows a unidirectional path
Starting at P0, when OC cells are postmitotic, Rbl1/p107 expression was observed in both inner hair cell (IHC)- and outer hair cell (OHC)-associated SCs, as well as in a subset of cells in the spiral limbus (Figures 1(A) and (B))
No expression was detected in the OHCs (Figures 1(A)-(C)), some Rbl1/p107-positive reaction was observed in the IHC nuclei, in the apical region (Figure 1(A)), as well as in Hensen’s cells (HeC) and Deiters’ cells (DC) (Figures 1(A), (B) and (D))
Summary
Differentiation of inner ear sensory hair cells (HCs) and their associated non-sensory supporting cells (SCs) follows a unidirectional path. Many genes regulating cell proliferation, differentiation, and maturation elsewhere in the body are thought to function in the auditory system. There has been growing interest in determining the role of the retinoblastoma (pRB) family, a.k.a. pocket proteins (Rb1, Rbl1/p107, Rbl2/p130), in the inner ear [2,3,4,5,6,7,8]. Loss of Rbl2/p130 is associated with SCs and HC proliferation in limited regions of the cochlea. The clear distinctions and similarities between Rb1 and Rbl2/p130 loss-of-function in the inner ear suggest both redundant and non-redundant roles of the pRB family. All three pRBs are expressed at relatively low levels in the primordial
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