β-Catenin Is Required for Hair-Cell Differentiation in the Cochlea

Abstract

The development of hair cells in the auditory system can be separated into steps; first, the establishment of progenitors for the sensory epithelium, and second, the differentiation of hair cells. Although the differentiation of hair cells is known to require the expression of basic helix-loop-helix transcription factor, Atoh1, the control of cell proliferation in the region of the developing cochlea that will ultimately become the sensory epithelium and the cues that initiate Atoh1 expression remain obscure. We assessed the role of Wnt/␤-catenin in both steps in gain-and loss-of-function models in mice. The canonical Wnt pathway mediator, ␤-catenin, controls the expression of Atoh1. Knock-out of ␤-catenin inhibited hair-cell, as well as pillar-cell, differentiation from sensory progenitors but was not required to maintain a hair-cell fate once specified. Constitutive activation of ␤-catenin expanded sensory progenitors by inducing additional cell division and resulted in the differentiation of extra hair cells. Our data demonstrate that ␤-catenin plays a role in cell division and differentiation in the cochlear sensory epithelium.

Notch-Wnt-Bmp crosstalk regulates radial patterning in the mouse cochlea in a spatiotemporal manner

“…The increase in IHCs following day 1 CHIR treatment was likely to be caused by directly upregulating Atoh1, a documented Wnt target gene (Kuo et al, 2015;Shi et al, 2010Shi et al, , 2014. At the time of CHIR treatment, Atoh1 expression was already ongoing and Wnt activation boosted it further.…”

“…Genetic manipulations of the pathway had previously revealed that Wnts function at multiple stages in the embryonic inner ear, beginning with otic induction (Jayasena et al, 2008). Inducible Cre drivers allowed further development of the cochlea before β-catenin was knocked out or overexpressed (Shi et al, 2014). However, it is challenging to correlate phenotypic changes in the OC with specific Wnt ligands or their immediate target genes due to inherent delays between induction, Cre recombination and β-catenin turnover.…”

New treatment options for hearing loss

“…ATOH1 must be activated by the canonical WNT effector β-catenin at the appropriate time for hair cell differentiation to proceed [108][109][110] . WNT ligands are thought to be secreted from cells that are outside the sensory epithelium 111 , and their production may cease in the adult ear.…”

LSD1 is Required for Hair Cell Regeneration in Zebrafish

“…Conversely, inhibition of this signaling suppresses proliferation and causes a dramatic decrease in hair cell numbers [68,71]. Therefore, multiple recent studies have focused on regulating the Wnt pathway as a potential target for treating hearing loss [7,[71][72][73][74][75][76][77][78]. A recent study examined the role of epigenetic regulation in colorectal tumorigenesis and found that LSD1 activates the Wnt/β-catenin signaling pathway by downregulating a negative regulator of the pathway, Dickkopf-1 [79].…”