Essential role of retinoblastoma protein in mammalian hair cell development and hearing

Sage, Cyrille; Huang, Meei Li; Vollrath, Melissa A.; Brown, M. Christian; Hinds, Philip W.; Corey, David P.; Vetter, Douglas E.; Chen, Zhengyi

doi:10.1073/pnas.0510631103

Cited by 115 publications

(136 citation statements)

References 41 publications

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“…Interestingly, we found no impairment in the expression of either blood vessel or cardiac differentiation markers in the DKOs; however, our analysis revealed a significant increase in the percentage of proliferating endothelial cells in both the Tie2-Cre and Mox2-Cre DKOs. This raises the possibility that loss of pRb and p107 allows differentiated cells to remain in cycle, as has been reported previously for Rb-deficient hair cells (22).…”

Section: Discussionsupporting

confidence: 63%

Mutation of p107 exacerbates the consequences of Rb loss in embryonic tissues and causes cardiac and blood vessel defects

Berman

West

Danielian

et al. 2009

Proc. Natl. Acad. Sci. U.S.A.

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The retinoblastoma tumor-suppressor protein, pRb, is a member of the pocket protein family that includes p107 and p130. These proteins have well-defined roles in regulating entry into and exit from the cell cycle and also have cell cycle-independent roles in facilitating differentiation. Here we investigate the overlap between pocket protein's function during embryonic development by using conditional mutant alleles to generate Rb;p107 doublemutant embryos (DKOs) that develop in the absence of placental defects. These DKOs die between e13.5 and e14.5, much earlier than either the conditional Rb or the germline p107 single mutants, which survive to birth or are largely viable, respectively. Analyses of the e13.5 DKOs shows that p107 mutation exacerbates the phenotypes resulting from pRb loss in the central nervous system and lens, but not in the peripheral nervous system. In addition, these embryos exhibit novel phenotypes, including increased proliferation of blood vessel endothelial cells, and heart defects, including double-outlet right ventricle (DORV). The DORV is caused, at least in part, by a defect in blood vessel endothelial cells and/or heart mesenchymal cells. These findings demonstrate novel, overlapping functions for pRb and p107 in numerous murine tissues.cell cycle ͉ heart ͉ p107 ͉ retinoblastoma

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Section: Discussionsupporting

confidence: 63%

Mutation of p107 exacerbates the consequences of Rb loss in embryonic tissues and causes cardiac and blood vessel defects

Berman

West

Danielian

et al. 2009

Proc. Natl. Acad. Sci. U.S.A.

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“…Knockdown of the cell cycle exit regulators Cdkn1b (p27/Kip1), p19/Ink4d, and pRb led to the initiation of cell cycle reentry and the differentiation of hair cells in injured epithelia in mice (20,21,64,76,77). Unfortunately, these ectopic hair cells cannot be maintained and eventually apoptose.…”

Section: Discussionmentioning

confidence: 99%

Gene-expression analysis of hair cell regeneration in the zebrafish lateral line

Jiang

Romero‐Carvajal

Haug

et al. 2014

Proc. Natl. Acad. Sci. U.S.A.

133

151

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Deafness caused by the terminal loss of inner ear hair cells is one of the most common sensory diseases. However, nonmammalian animals (e.g., birds, amphibians, and fish) regenerate damaged hair cells. To understand better the reasons underpinning such disparities in regeneration among vertebrates, we set out to define at high resolution the changes in gene expression associated with the regeneration of hair cells in the zebrafish lateral line. We performed RNA-Seq analyses on regenerating support cells purified by FACS. The resulting expression data were subjected to pathway enrichment analyses, and the differentially expressed genes were validated in vivo via whole-mount in situ hybridizations. We discovered that cell cycle regulators are expressed hours before the activation of Wnt/β-catenin signaling following hair cell death. We propose that Wnt/β-catenin signaling is not involved in regulating the onset of proliferation but governs proliferation at later stages of regeneration. In addition, and in marked contrast to mammals, our data clearly indicate that the Notch pathway is significantly down-regulated shortly after injury, thus uncovering a key difference between the zebrafish and mammalian responses to hair cell injury. Taken together, our findings lay the foundation for identifying differences in signaling pathway regulation that could be exploited as potential therapeutic targets to promote either sensory epithelium or hair cell regeneration in mammals.signaling pathway analysis | RNA sequencing | neuromast | Jak/Stat3 | cdkn1b

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“…IHCs of Pou4f3-α10 mice express α10 mRNA after the onset of hearing It has been reported that the Pou4f3 transcription factor is expressed in hair cells from early embryonic until adult stages (Erkman et al 1996) and that Cre expression driven by the Pou4f3 promoter starts as early as embryonic day 13.5 in a transgenic mouse (Sage et al 2006). Thus, the use of the Pou4f3 promoter has become a useful tool for transgenic expression of genes in cochlear hair cells.…”

Section: Resultsmentioning

confidence: 99%

“…The Pou4f3-α10 transgenic mice were generated using a construct like that previously engineered to drive hair cell expression of Cre recombinase (Sage et al 2006). As shown in Figure 1A, a 1.5-kb fragment containing the cDNA encoding the α10 nAChR (Elgoyhen et al 2001) was subcloned into pSP73 (Promega Corp, Madison, WI, USA).…”

Section: Generation Of Pou4f3-α10 Transgenic Micementioning

confidence: 99%

Constitutive Expression of the α10 Nicotinic Acetylcholine Receptor Subunit Fails to Maintain Cholinergic Responses in Inner Hair Cells After the Onset of Hearing

Taranda

Ballestero

Hiel

et al. 2009

JARO

Self Cite

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Efferent inhibition of cochlear hair cells is mediated by α9α10 nicotinic cholinergic receptors (nAChRs) functionally coupled to calcium-activated, small conductance (SK2) potassium channels. Before the onset of hearing, efferent fibers transiently make functional cholinergic synapses with inner hair cells (IHCs). The retraction of these fibers after the onset of hearing correlates with the cessation of transcription of the Chrna10 (but not the Chrna9) gene in IHCs. To further analyze this developmental change, we generated a transgenic mice whose IHCs constitutively express α10 into adulthood by expressing the α10 cDNA under the control of the Pou4f3 gene promoter. In situ hybridization showed that the α10 mRNA is expressed in IHCs of 8-week-old transgenic mice, but not in wild-type mice. Moreover, this mRNA is translated into a functional protein, since IHCs from P8-P10 α10 transgenic mice backcrossed to a Chrna10 −/− background (whose IHCs have no cholinergic function) displayed normal synaptic and acetylcholine (ACh)-evoked currents in patch-clamp recordings. Thus, the α10 transgene restored nAChR function. However, in the α10 transgenic mice, no synaptic or ACh-evoked currents were observed in P16-18 IHCs, indicating developmental downregulation of functional nAChRs after the onset of hearing, as normally observed in wild-type mice. The lack of functional ACh currents correlated with the lack of SK2 currents. These results indicate that multiple features of the efferent postsynaptic complex to IHCs, in addition to the nAChR subunits, are down-regulated in synchrony after the onset of hearing, leading to lack of responses to ACh.

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Essential role of retinoblastoma protein in mammalian hair cell development and hearing

Cited by 115 publications

References 41 publications

Mutation of p107 exacerbates the consequences of Rb loss in embryonic tissues and causes cardiac and blood vessel defects

Mutation of p107 exacerbates the consequences of Rb loss in embryonic tissues and causes cardiac and blood vessel defects

Gene-expression analysis of hair cell regeneration in the zebrafish lateral line

Constitutive Expression of the α10 Nicotinic Acetylcholine Receptor Subunit Fails to Maintain Cholinergic Responses in Inner Hair Cells After the Onset of Hearing

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