The role of Wnt/β‐catenin signaling in proliferation and regeneration of the developing basilar papilla and lateral line

Abstract

Canonical Wnt/β-catenin signaling has been implicated in multiple developmental events including the regulation of proliferation, cell fate, and differentiation. In the inner ear, Wnt/β-catenin signaling is required from the earliest stages of otic placode specification through the formation of the mature cochlea. Within the avian inner ear, the basilar papilla (BP), many Wnt pathway components are expressed throughout development. Here, using reporter constructs for Wnt/β-catenin signaling, we show that this pathway is active throughout the BP (E6-E14) in both hair cells (HCs) and supporting cells. To characterize the role of Wnt/β-catenin activity in developing HCs, we performed gain- and loss-of-function experiments in vitro and in vivo in the chick BP and zebrafish lateral line systems, respectively. Pharmacological inhibition of Wnt signaling in the BP and lateral line neuromasts during the periods of proliferation and HC differentiation resulted in reduced proliferation and decreased HC formation. Conversely, pharmacological activation of this pathway significantly increased the number of HCs in the lateral line and BP. Results demonstrated that this increase was the result of up-regulated cell proliferation within the Sox2-positive cells of the prosensory domains. Furthermore, Wnt/β-catenin activation resulted in enhanced HC regeneration in the zebrafish lateral line following aminoglycoside-induced HC loss. Combined, our data suggest that Wnt/β-catenin signaling specifies the number of cells within the prosensory domain and subsequently the number of HCs. This ability to induce proliferation suggests that the modulation of Wnt/β-catenin signaling could play an important role in therapeutic HC regeneration.

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

“…Wnt/β-catenin signaling is required for proliferation in developing and regenerating neuromasts (26,48). Unexpectedly, the SPIA pathway analysis suggested that the Wnt/β-catenin pathway is inactive at 1 h after hair cell death (Table S3).…”

“…Wnt/β-catenin signaling controls stem cell maintenance, quiescence, and proliferation during mammalian epithelial hair cell, zebrafish fin, mammalian intestine, hydra head, and planarian regeneration (82)(83)(84)(85)(86). Importantly, Wnt/β-catenin also is crucial for regulating proliferation in developing and regenerating zebrafish neuromasts (26,48).…”

Sensory hair cell development and regeneration: similarities and differences

“…In this context, Wnt activators have been shown to increase the degree of regeneration after damage (Head et al, 2013;Jacques et al, 2014). Similarly, recent studies of the damaged neonatal mouse utricle revealed that Wnt/β-catenin activation increases both supporting cell proliferation and, subsequently, hair cell regeneration in vivo (Wang et al, 2015).…”

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].…”

“…This stimulation of proliferation results in a significant increase in the number of hair cells within both developing and regenerating neuromasts. 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].…”