Pvalb8, a Type of Oncomodulin, Regulates Neuromast Development and Auditory Function in Zebrafish

TL;DR

The study shows that pvalb8, a type of oncomodulin, is crucial for the development of hair cells and hearing in zebrafish.

Contribution

This is the first study to report the function of the oncomodulin lineage in fish and identify pvalb8 as a key regulator of hair cell development.

Findings

pvalb8 is highly expressed in supporting cells and hair cells in zebrafish.

Loss of pvalb8 leads to reduced neuromast size and hearing loss due to fewer hair cells.

Wnt signaling pathway activation rescues hair cell loss in pvalb8 mutants.

Abstract

What are the main findings?
pvalb8 is highly and specifically expressed in supporting cells and hair cells.The pvalb8 mutation causes developmental defects in neuromasts and significant hearing loss.Loss of pvalb8 suppresses supporting cell proliferation, limiting hair cell differentia-tion.Activation of the Wnt signaling pathway rescues the hair cell loss observed in pvalb8 mutants.

pvalb8 is highly and specifically expressed in supporting cells and hair cells.

The pvalb8 mutation causes developmental defects in neuromasts and significant hearing loss.

Loss of pvalb8 suppresses supporting cell proliferation, limiting hair cell differentia-tion.

Activation of the Wnt signaling pathway rescues the hair cell loss observed in pvalb8 mutants.

What is the implication of the main finding?
pvalb8 regulates the development of neuromast and hair cells by mediating the Wnt signaling pathway.

pvalb8 regulates the development of neuromast and hair cells by mediating the Wnt signaling pathway.

Congenital hearing loss, frequently resulting from defective hair cells, remains poorly understood due to the incomplete identification of key pathogenic genes. Oncomodulin (OCM) is a kind of calcium-binding protein (CaBP) that regulates diverse cellular processes and is thought to play crucial roles in auditory function. In teleost fish, parvalbumin 8 (pvalb8) and parvalbumin 9 (pvalb9) belong to the oncomodulin lineage and are highly expressed in hair cells. In this study, we first reported the oncomodulin lineage function in fish and identified pvalb8 as an essential regulator of hair cell development. Single-cell RNA sequencing (scRNA-seq) and whole-mount in situ hybridization (WISH) revealed that pvalb8 is highly and specifically expressed in supporting cells and hair cells. Functional loss of pvalb8, achieved via CRISPR/Cas9 knockout or morpholino knockdown, resulted in reduced neuromast size and a significant decrease in neuromast hair cell number, leading to auditory behavioral deficits. In addition, pvalb9 mutants exhibited hair cell defects similar to those observed in pvalb8 mutants, including a significant reduction in hair cell number. Moreover, pvalb8 loss strongly inhibited the proliferation of supporting cells, which likely accounts for the reduced number of differentiated hair cells. The expression levels of Wnt target genes, axin2, ccnd1, and myca, were all significantly reduced in pvalb8 mutants compared to control zebrafish, while activation of the Wnt signaling pathway rescued the hair cell loss observed in pvalb8 mutants, indicating that pvalb8 promotes hair cell development via Wnt-dependent proliferative signaling. These findings highlight pvalb8 as a critical factor in the regulation of auditory hair cell formation and function in zebrafish, offering new insights into the role of oncomodulin lineage in sensory cell development.

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