Abstract
In the developing cochlea, Wnt/β-catenin signaling positively regulates the proliferation of precursors and promotes the formation of hair cells by up-regulating Atoh1 expression. Not much, however, is known about the regulation of Wnt/β-catenin activity in the cochlea. In multiple tissues, the activity of Wnt/β-catenin signaling is modulated by an interaction between LGR receptors and their ligands from the R-spondin family. The deficiency in Lgr4 and Lgr5 genes leads to developmental malformations and lethality. Using the Lgr5 knock-in mouse line we show that loss of LGR5 function increases Wnt/β-catenin activity in the embryonic cochlea, resulting in a mild overproduction of inner and outer hair cells (OHC). Supernumerary hair cells are likely formed due to an up-regulation of the “pro-hair cell” transcription factors Atoh1, Nhlh1, and Pou4f3. Using a hypomorphic Lgr4 mouse model we showed a mild overproduction of OHCs in the heterozygous and homozygous Lgr4 mice. The loss of LGR4 function prolonged the proliferation in the mid-basal turn of E13 cochleae, causing an increase in the number of SOX2-positive precursor cells within the pro-sensory domain. The premature differentiation of hair cells progressed in a medial to lateral gradient in Lgr4 deficient embryos. No significant up-regulation of Atoh1 was observed following Lgr4 deletion. Altogether, our findings suggest that LGR4 and LGR5 play an important role in the regulation of hair cell differentiation in the embryonic cochlea.
Highlights
Hearing is the process by which mechanical sound stimuli are transduced into electrical signals within the auditory nerve and transmitted to the cortex
LGR5 is expressed in the pro-sensory cells that are positive for Wnt/β-catenin activity and give rise to both hair cells and the supporting cells (Chai et al, 2011; Jacques et al, 2012)
The number of outer hair cells (OHC) in the mid-basal region increased from ± 1.7 (n = 3) in wild type mice and ± 1.5 (n=3, p ≤ 0.05) in heterozygous Lgr5-eGFP mice to 208 ± 8.1 (n = 3, p ≤ 0.05) in homozygous Lgr5-eGFP mice, whereas the number of OHCs remained similar in the apical and basal turns in all genotypes (Figure 1C)
Summary
Hearing is the process by which mechanical sound stimuli are transduced into electrical signals within the auditory nerve and transmitted to the cortex. The sensory epithelium is comprised of sensory hair cells and their surrounding auxiliary supporting cells. Both cell types originate from a progenitor pool of ‘pro-sensory’ cells all of which express the transcription factor SOX2, the Notch ligand Jagged, and the cell cycle inhibitor p27K IP1 (Adam et al, 1998; Chen and Segil, 1999; Morrison et al, 1999; Kiernan et al, 2005; Brooker et al, 2006). A subset of pro-sensory cells up-regulate ATOH1, LGR4/5 in the Developing Cochlea a bHLH transcription factor, and differentiates into hair cells (Bermingham et al, 1999; Zheng and Gao, 2000; Woods et al, 2004; Cotanche and Kaiser, 2010). Hair cells instruct their neighbor cells to down-regulate ATOH1 and form the supporting cells (Lanford et al, 1999; Zine et al, 2001; Jeon et al, 2011)
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