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

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.